CN110167941A - Substituted fused heteroaryl compounds are as kinase inhibitor and its application - Google Patents

Abstract

The present invention provides the fused heteroaryl compounds replaced as kinase inhibitor and its application.Specifically, the present invention provides the compound or its officinal salt or prodrug of following formula I, wherein A₁‑A₄, B₁‑B₃, D₁‑D₄And R₁‑R₃It is defined herein.The compound of Formulas I is kinase inhibitor.Therefore, the compound of the present invention can be used for treating because of clinical disease caused by DDR functional defect, such as cancer.

Description

Substituted fused heteroaryl compounds are as kinase inhibitor and its application Technical field

The invention belongs to field of medicinal chemistry.The present invention is more particularly directed to substituted fused heteroaryl compounds as kinase inhibitor, including ATM kinases inhibitor, and its application.

Background technique

Mammalian cell faces the challenge of the outside for largely causing DNA damage and inside daily, this includes the mutation of DNA base.It includes leading to the generation of malignant tumour that these mutation less serious case, which causes the change on cell function, and severe one directly contributes cell death.Therefore mammalian cell has evolved a set of fine DNA damage repair mechanism (DNA damage response, DDR) to cope with these challenges.This mechanism is detected by brief cell cycle arrest to be damaged with DNA plerosis to ensure the stabilization of genome to the survival of cell.

DDR and cancer have inextricably involved relationship.Defect on scientific research discovery DDR repair mechanism can lead to the generation of cancer in stage construction, such as the base mutation of DDR gene has been found the generation for leading to kinds cancer, this include carry BRCA1 or BRCA2 gene base mutation women suffer from breast cancer it is more much higher than the crowd not being mutated with the risk of oophoroma.And BRCA1 and BRCA2 are exactly the important component based on the fracture of homologous recombination repair DNA double chain in DDR.Research it has also been found that in Several Kinds of Malignancy cell DDR or adjust the cell cycle key protein missing or function lose, this includes p53, ATM, ATR, BRCA1/2 etc..

The forfeiture exploitation new type anticancer target therapeutic agent of understanding recently as the reach of science and to cell DDR mechanism, mutation and function for DDR constitutive protein causes the great interest of people.For example PARP inhibitor is by inhibiting the single-stranded repair mechanism of DNA damage that can pointedly kill the cancer cell of BRCA1/2 mutation.This mechanism of action is referred to as " synthetic lethal ".

ATM kinases is one of important composition albumen of DDR, belongs to the relevant silk amino acid of PI3K-/Su An pka acid family.ATM kinase gene is cloned when nineteen ninety-five studying ataxia telangiectasia syndrome.ATM gene is located on human chromosome 11q22-23, is the coded sequence including 66 exons and 9168 bases.ATM kinases is the larger protein of an about 350kDa molecular weight.ATM kinases is one of important component of DDR.ATM kinases is activated when DNA damage causes double-strand break.Its function reaches cell cycle transitions point by phosphorylation downstream albumen and pauses, and repair by DNA of the homologous recombination to damage or enters Apoptosis Mechanism (Weber and Ryan, 2016).

ATM kinase signal transduction can rough segmentation be two kinds of mechanism: typical mechanism by DNA double chain be broken activate.When cell detection to DNA double chain is broken, ATM kinases is transported to fracture location and activates.Although detailed activation mechanism is also not very clear, activation includes that active monomer (Bakkenist et al., 2003), the autophosphorylation and acetylation in the site Ser1981 and other sites are split as from homodimer.The further phosphorylation stream substrates of ATM kinases after activation, this includes cell cycle checkpoint albumen (such as Chk1 and Chk2), DNA repair protein (BRCA1 and RAD51) or Apoptosis pathway protein (p53).Studies have shown that the albumen being phosphorylated caused by after DNA double chain fracture has 700 kinds or more (Choi, Kipps and Kurzrock, 2016).In addition, ATM also participates in not direct function relevant with DNA damage, for example it is metabolized, answering pressure etc., these functions are commonly known as atypia mechanism (Cremona et al., 2013).

Anti-cancer drugs, which is researched and developed, as drug targets using ATM kinases relies primarily on both sides consideration.It is typically based on DNA damage thus the cancer cell fast to differentiation causes radiotherapy or cell toxicant based chemotherapy drug, such as topoisomerase enzyme inhibitor, DNA methylation drug of toxicity etc. since the presence of DDR substantially reduces cytotoxicity caused by it.Therefore joint inhibits the inhibitor of DDR constitutive protein function, such as PARP inhibitor, ATM inhibitor that can greatly enhance the drug effect of this kind of drug.Gilardini Montani MS et al. (J Exp Clin Cancer Res, 2013,32:95) research shows that reduce ATM expression can enhance breast cancer cell to the sensibility of PARP inhibitor, to provide theoretical basis a possibility that ATM inhibitor and PARP inhibitor for treating breast cancer is used in combination.Furthermore, Kubota E et al. (Cell Cycle, 2014,13 (13): 2129-2137) then find that ATM protein expression level has significant correlation to the sensibility of PARP inhibitor olaparib in stomach cancer cell, sensibility of the stomach cancer cell to olaparib of p53 inactivation is enhanced using small molecule ATM inhibitor.Therefore ATM inhibitor is used in combination and PARP inhibitor is possibly used for treatment gastric cancer.In addition, can be used alone to the cancer cell for having DDR functional defect by synthetic lethal mechanism ATM kinase inhibitor, for particular patient crowd exploitation at targeted anticancer medicine, there is good drug efficacy, the low feature of toxicity.

WO2012034526 discloses condensed heteroaryl compound as P13K kinase inhibitor.Wherein A ¹It is N or CH；A ⁴And A ⁵It independently is N or CR ², R ²Independently selected from hydrogen, alkyl, alkenyl, alkynyl and aryl etc.；A ²、A ³The heteroatomic quinary heteroaryl or quinary heterocyclic radical that N, O and S are selected from containing 1-4 are formed together with B ring； Indicate singly-bound or double bond；R ¹It is heteroaryl.

WO2015170081 discloses imidazoquinolie ketone as ATM kinase inhibitor.Wherein Q is cyclobutyl or cyclopenta or oxa- fourth ring group, tetrahydrofuran base or oxacyclohexyl；R ¹It is methyl；R ²It is hydrogen or methyl；Or R ¹With R ²Azete piperidinyl, pyrroles's piperidinyl or piperidyl is collectively formed；R ³It is hydrogen or fluorine；R ⁴It is hydrogen or methyl；And R ⁵It is hydrogen or fluorine.

Degorce SL et al. (J Med Chem, 2016, a series of 3- quinoline formyl amine 59:6281-6292) are reported as ATM kinase inhibitor, and observe the good drug effect of ATM kinase inhibitor Yu Irinotecan (irinotecan) drug combination in animal model.

Summary of the invention

Such as structural formula I, shown in Formula II and formula III, the present invention provides novel substituted fused heteroaryl compounds as kinase inhibitor, especially ATM kinase inhibitor.

The present invention also provides the Formulas I comprising an effective amount, the Pharmaceutical composition of Formula II or formula III compound is used to treating cancer.

In one embodiment, the Pharmaceutical composition can also contain one or more pharmaceutical acceptable carrier or diluent, be used to treating cancer.

In one embodiment, the Pharmaceutical composition also officinal salt containing at least one known anticancer drug or the anticancer drug, is used to treating cancer.

Also relate to structural formula I, the preparation method of the compounds of Formula II and formula III.

Specific embodiment

Shown in formula I, present invention discover that novel substituted fused heteroaryl compounds are as kinase inhibitor, especially ATM kinase inhibitor.

It should be understood that various embodiments described herein feature can any combination, form the technical solution of this paper；Any embodiment described herein is suitable for the definition of each group herein, for example, being suitable for any embodiment described herein to the definition of the substituent group of alkyl herein, unless the clearly defined substituent group of alkyl of the embodiment.

Specifically, compound for use in the present invention is compound of formula I or its officinal salt or prodrug:

Wherein, A ₁And A ₂It is respectively independently C or N；

A ₃And A ₄It is respectively independently N, O, S or CR '；

And including A ₁-A ₄A ring be containing 1-3 is heteroatomic can substituted 5 unit's heteroaryl；

B ₁-B ₃Respectively stand alone as N or CR "；

D ₁-D ₄Respectively stand alone as N or CR " '；

R ₁Being can substituted alkyl, alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl；

R ₂It is hydrogen, it can substituted alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl；

R ', R ", R " ' and R ₃Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl, carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group.

In one or more embodiments, A in compound of formula I ₁For N.In one or more embodiments, A in compound of formula I ₂For C.

In aforementioned one or more embodiments, in compound of formula I, A ₁For N, A ₂For C.

In aforementioned one or more embodiments, in compound of formula I, A ₃And A ₄Respectively N.

In aforementioned one or more embodiments, in compound of formula I, contain A ₁-A ₄Ring be triazole ring, imidazole ring or pyrrole ring.

In aforementioned one or more embodiments, B in compound of formula I ₁For CR ", it is more preferred to B ₁For CH.In one or more embodiments, R in compound of formula I ₃It is hydrogen.In one or more embodiments, in compound of formula I, R ' is H.

In aforementioned one or more embodiments, in compound of formula I, B ₁For CH, R ' and R ₃For H.In one or more embodiments, B ₂And B ₃Respectively stand alone as CH or N.

In aforementioned one or more embodiments, B in compound of formula I ₃For CH.

In aforementioned one or more embodiments, B in compound of formula I ₃For CH, B ₁And B ₂For CH.

In aforementioned one or more embodiments, B in compound of formula I ₃For N.

In aforementioned one or more embodiments, B in compound of formula I ₃For N, B ₁And B ₂For CH.

In aforementioned one or more embodiments, in compound of formula I, A ₁For N, A ₂For C, B ₁For CH, R ' and R ₃For H.

In aforementioned one or more embodiments, in compound of formula I, A ₁For N, A ₂For C, B ₁-B ₃For CH, R ' and R ₃For H.

In aforementioned one or more embodiments, in compound of formula I, A ₁For N, A ₂For C, B ₁And B ₂For CH, B ₃For N, R ' and R ₃For H.

In aforementioned one or more embodiments, in compound of formula I, contain B ₁-B ₃Ring be phenyl ring or pyridine ring.Preferably, described to contain B ₁-B ₃Ring be phenyl ring or B ₃For the pyridine ring of N.

In aforementioned one or more embodiments, in compound of formula I, contain A ₁And A ₂6 member rings be pyridine ring or pyrimidine ring, preferably pyridine ring.

In aforementioned one or more embodiments, in compound of formula I, contain A ₁-A ₄A ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, imidazo [1,5-c] quinazolyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl.

In aforementioned one or more embodiments, in compound of formula I, R ₁On substituent group be selected from C _1-6Alkyl, heterocycle, aryl, heteroaryl and-NR ₉R ₁₀, wherein the quantity of substituent group is 1-4, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, R ₁Being can substituted alkyl, heterocycle, aryl or heteroaryl；Wherein, substituent group on alkyl can be 1 heterocycle, such as tetrahydrofuran base, THP trtrahydropyranyl, pyranose, piperidyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, morpholinyl, pyrazolidinyl and pyrazolinyl；Substituent group on heterocycle, aryl and heteroaryl can be 1-4 selected from C _1-6Alkyl and-NR ₉R ₁₀Substituent group.

In aforementioned one or more embodiments, in compound of formula I, R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle (such as tetrahydrofuran base, THP trtrahydropyranyl, pyranose, piperidyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, morpholinyl, pyrazolidinyl and pyrazolinyl) _1-6Alkyl；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, in compound of formula I, R ₁Selected from unsubstituted or optionally by 1-2 C _1-4It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-2 C _1-4It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-2 C _1-4Alkyl-substituted morpholinyl and C is optionally selected from by 1-3 _1-4Alkyl-substituted piperazinyl.Preferred R ₁Selected from can substituted heterocycle, comprising:

It is further preferable that R ₁It is selected from:

In aforementioned one or more embodiments, compound of formula I contains D ₁-D ₄Ring be can substituted pyridine ring, can substituted phenyl ring, can substituted pyrimidine ring or can substituted pyridine ring.Preferably, the compound of formula I contains D ₁-D ₄Ring be can substituted phenyl ring.In certain embodiments, this contains D ₁-D ₄Ring on substituent group remove R ₂Outside, further include R " '.

In aforementioned one or more embodiments, in compound of formula I, D ₁For CH, D ₂For N, D ₃For N and D ₄For CH；In certain embodiments, D ₁For N, D ₂For CH, D ₃For CH, D ₄For CH；In certain embodiments, D ₁For CH, D ₂For N, D ₃For CH, D ₄For CH；In certain embodiments, D ₁For CR " ', D ₂For CR " ', D ₃For CR " ', D ₄For CH；In certain embodiments, D ₁For CH, D ₂For CR " ', D ₃For CR " ', D ₄For CH；In certain embodiments, D ₁For CH, D ₂For CR " ', D ₃For CH, D ₄For CH；In certain embodiments, D ₁For CR " ', D ₂For CR " ', D ₃For CR " ', D ₄For CR " '；D ₁For CR " ', D ₂For CR " ', D ₃For CH, D ₄For CH, wherein preferably, R " ' respectively stands alone as H, halogen, C _1-4Alkyl and halogenated C _1-4Alkyl.It is further preferable that R " ' respectively stand alone as halogen and halogenated C _1-4Alkyl.

In aforementioned one or more embodiments, in compound of formula I, R ₂Upper substituent group can be selected from-NR ₉R ₁₀、C _1-4Alkyl and-NR ₉R ₁₀Substituted C _1-6Alkyl, wherein the quantity of substituent group can be 1-4, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.

In aforementioned one or more embodiments, in compound of formula I, R ₂It is selected from: hydrogen ,-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Or-NR ₉R ₁₀Substituted C _1-6Alkyl-substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base, optionally by-NR ₉R ₁₀Or-NR ₉R ₁₀Substituted C _1-6Alkyl-substituted piperidyl, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl and-NR ₉R ₁₀Substituted C _1-6Alkoxy.Preferred R ₂Include:

It is further preferable that R ₂It is selected from:

Preferred compound of the present invention wherein one group be expressed as Formula II compound or pharmaceutically acceptable salt thereof or prodrug:

Wherein, A ₂-A ₄, B ₂-B ₃, D ₁-D ₄And R ₁-R ₃As Formulas I defines；

R ₄Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl, carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group.

In one or more embodiments of Formula II compound, the A ₂-A ₄, B ₂-B ₃, D ₁-D ₄And R ₁-R ₃Respectively as described in the embodiment of any one aforementioned Formulas I.

In aforementioned one or more embodiments, R in Formula II compound ₃And R ₄It is hydrogen.

In aforementioned one or more embodiments, A in Formula II compound ₂For C.

In aforementioned one or more embodiments, in Formula II compound, A ₃And A ₄Respectively N.

In aforementioned one or more embodiments, in Formula II compound, contain A ₂-A ₄Ring be triazole ring, imidazole ring or pyrrole ring.

In aforementioned one or more embodiments, in Formula II compound, R ' is H.

In aforementioned one or more embodiments, in Formula II compound, A ₂For C, R ' and R ₃For H.

In one or more embodiments, in Formula II compound, B ₂And B ₃Respectively stand alone as CH or N.

In aforementioned one or more embodiments, in Formula II compound, contain B ₂-B ₃Ring be phenyl ring or pyridine ring.Preferably, described to contain B ₂-B ₃Ring be phenyl ring or B ₃For the pyridine ring of N.

In aforementioned one or more embodiments, in Formula II compound, contain A ₂6 member rings be pyridine ring.

In aforementioned one or more embodiments, in Formula II compound, contain A ₂-A ₄Ring, contain A ₂6 member rings with contain B ₂-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl.

In aforementioned one or more embodiments, in Formula II compound, R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle (such as tetrahydrofuran base, THP trtrahydropyranyl, pyranose, piperidyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, morpholinyl, pyrazolidinyl and pyrazolinyl) _1-6Alkyl；R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, in compound of formula I, R ₁Selected from unsubstituted or optionally by 1-2 C _1-4It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-2 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-2 C _1-4Alkyl-substituted morpholinyl and C is optionally selected from by 1-3 _1-4Alkyl-substituted piperazinyl.Preferred R ₁Selected from can substituted heterocycle, comprising:

It is further preferable that R ₁It is selected from:

In aforementioned one or more embodiments, Formula II compound contains D ₁-D ₄Ring be can substituted pyridine ring, can substituted phenyl ring, can substituted pyrimidine ring or can substituted pyridine ring.Preferably, the compound of formula I contains D ₁-D ₄Ring be can substituted phenyl ring.It is further preferable that described contain D ₁-D ₄Ring be D ₁And/or D ₂" ' the phenyl ring or D replaced by R ₂And/or D ₃" ' the phenyl ring replaced by R.Preferably, R " ' is selected from H, halogen, C _1-4Alkyl and halogenated C _1-4Alkyl.It is further preferable that R " ' it is selected from halogen and halogenated C _1-4Alkyl.

In aforementioned one or more embodiments, in Formula II compound, R ₂It is selected from: hydrogen ,-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NHR ₉, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base, optionally by-NR ₉R ₁₀Or-NR ₉R ₁₀Substituted C _1-6Alkyl-substituted piperidyl, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl and-NR ₉R ₁₀Substituted C _1-6Alkoxy.Preferred R ₂Include:

It is further preferable that R ₂It is selected from:

Preferred compound of the present invention wherein one group be expressed as formula III a or formula III b (formula III) compound or pharmaceutically acceptable salt thereof or prodrug:

Wherein, A ₂-A ₄, B ₂-B ₃, D ₁, D ₃-D ₄And R ₁-R ₄As Formulas I and Formula II define；

For formula III b, R ₅-R ₈Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl, carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group.

In one or more embodiments of formula III a and IIIb compound, the A ₂-A ₄, B ₂-B ₃, D ₁, D ₃-D ₄And R ₁-R ₃Respectively as described in the embodiment of any one aforementioned Formulas I or Formula II.

In aforementioned one or more embodiments, R in formula III a compound ₃And R ₄It is hydrogen.In one or more embodiments, R in formula III b compound ₅-R ₈It is hydrogen.

In one or more embodiments, R in formula III b compound ₅And R ₆Respectively stand alone as H, halogen, C _1-4Alkyl and halogenated C _1-4Alkyl.

In one or more embodiments, R in formula III b compound ₅And R ₆Respectively stand alone as halogen and halogenated C _1-4Alkyl.

In one or more embodiments, R in formula III b compound ₆And R ₇Respectively stand alone as H, halogen, C _1-4Alkyl and halogenated C _1-4Alkyl.

In aforementioned one or more embodiments, A in formula III a or IIIb compound ₂For C.

In aforementioned one or more embodiments, in formula III a or IIIb compound, A ₃And A ₄Respectively N.

In aforementioned one or more embodiments, in formula III a or IIIb compound, contain A ₂-A ₄Ring be triazole ring, imidazole ring or pyrrole ring.

In aforementioned one or more embodiments, in formula III a or IIIb compound, R ' is H.

In aforementioned one or more embodiments, in formula III a or IIIb compound, A ₂For C, R ' and R ₃For H.

In aforementioned one or more embodiments, in formula III a or IIIb compound, contain B ₂-B ₃Ring be phenyl ring or pyridine ring.Preferably, described to contain B ₂-B ₃Ring be phenyl ring or B ₃For the pyridine ring of N.

In aforementioned one or more embodiments, in formula III a or IIIb compound, contain A ₂6 member rings be pyridine ring.

In aforementioned one or more embodiments, in formula III a or IIIb compound, contain A ₂-A ₄Ring, contain A ₂6 member rings with contain B ₂-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl.In preferred embodiments, contain A ₂-A ₄Ring, contain A ₂6 member rings with contain B ₂-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl or pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl.

In aforementioned one or more embodiments, in formula III a or IIIb compound, R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle (such as tetrahydrofuran base, THP trtrahydropyranyl, pyranose, piperidyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, morpholinyl, pyrazolidinyl and pyrazolinyl) _1-6Alkyl；R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, in compound of formula I, R ₁Selected from unsubstituted or optionally by 1-2 C _1-4It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-2 C _1-4Alkyl-substituted piperidyl and C is optionally selected from by 1-3 _1-4Alkyl-substituted piperazinyl.Preferred R ₁Selected from can substituted heterocycle, comprising:

It is further preferable that R ₁It is selected from:

In aforementioned one or more embodiments, in formula III a compound, contain D ₁-D ₄Ring be can substituted pyridine ring, can substituted pyrimidine ring or can substituted pyridine ring.It should be understood that herein, removing R ₂Outside, this contains D ₁-D ₄Ring on substituent group may also include R " '.Preferred R " ' can be selected from halogen, C _1-4Alkyl and halogenated C _1-4Alkyl.

In aforementioned one or more embodiments, in formula III a or IIIb compound, R ₂It is selected from: hydrogen ,-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NHR ₉, optionally by 1-3 C _{1- 4}Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base, optionally by-NR ₉R ₁₀Or-NR ₉R ₁₀Substituted C _1-6Alkyl-substituted piperidyl, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl and-NR ₉R ₁₀Substituted C _1-6Alkoxy.Preferred R ₂Include:

It is further preferable that R ₂It is selected from:

In aforementioned one or more embodiments, in Formulas I, II, IIIa and IIIb, the substituent group on A ring is selected from one or more of the substituent group of heteroaryl as described herein.

In aforementioned one or more embodiments, in Formulas I, II, IIIa and IIIb, R ₁The alkyl, alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl can be chosen alkyl described herein, alkoxy, amino, carbocylic radical, heterocycle, and one or more in the substituent group of aryl or heteroaryl replace.

In aforementioned one or more embodiments, in Formulas I, II, IIIa and IIIb, R ₂The alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl can be chosen alkoxy described herein, amino, carbocylic radical, heterocycle, and one or more in the substituent group of aryl or heteroaryl replace.

In aforementioned one or more embodiments, in Formulas I, II, IIIa and IIIb, R ', R ", R " ' and R ₃It is described can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl and can the substituent group of substituted alkylthio group be selected from one or more of amino as described herein, alkoxy, alkyl and substituent group of alkylthio group.

In aforementioned one or more embodiments, in formula III b, R ₅-R ₈It is described can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl and can the substituent group of substituted alkylthio group be selected from one or more of amino as described herein, alkoxy, alkyl and substituent group of alkylthio group.

In aforementioned one or more embodiments, in formula III, preferred COMPOUNDS EXAMPLE is formula III b compound.

In aforementioned one or more embodiments, preferred COMPOUNDS EXAMPLE is formula III b compound, wherein A ₂For C；A ₃And A ₄For N；B ₂For CH；B ₃For N or CH；R ₆For alkylhalide group or halogen；R ₅、R ₇And R ₈For H or halogen；R ₁For can substituted heterocycle；R ₂For can substituted heterocycle, or by-NR ₉R ₁₀Substituted C _1-6Alkoxy；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.It is highly preferred that B ₃For N or CH；R ₆For CF ₃, F, Br or Cl；R ₅、R ₇And R ₈For H or halogen；R ₂For it is described can substituted heterocycle, or by-NR ₉R ₁₀Substituted C _1-6Alkoxy.

In aforementioned one or more embodiments, Formulas I, Formula II, formula III a and the preferred COMPOUNDS EXAMPLE of formula III b include but is not limited to:

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 1)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine (embodiment 2)；

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 3)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 4)；

N, N- dimethyl -3- ((6- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridin-3-yl) oxygroup) -1- propylamine (embodiment 5)；

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrimidine -2-base) oxygroup) -1- propylamine (embodiment 6)；

N, N- dimethyl -3- ((2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrimidine -5- base) oxygroup) -1- propylamine (embodiment 7)；

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrazine -2- base) oxygroup) -1- propylamine (embodiment 8)；

N, N- dimethyl -2- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) ethamine (embodiment 9)；

N- (3- (dimethylamino) propyl) -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) aniline (embodiment 10)；

N- (3- (dimethylamino) propyl)-N- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) aniline (embodiment 11)；

N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 12)；

8- (4- (4- methylpiperazine-1-yl) phenyl) -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 13)；

1- (tetrahydro -2H- pyrans -4- base) -8- (4- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) phenyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 14)；

N, N- dimethyl -1- (5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) piperidines -4- amine (embodiment 15)；

8- (6- (4- methylpiperazine-1-yl) pyridin-3-yl) -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 16)；

1- (tetrahydro -2H- pyrans -4- base) -8- (6- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyridin-3-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 17)；

N, N- dimethyl -4- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) cyclohexylamine (embodiment 18)；

N, N- dimethyl -4- (5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) cyclohexylamine (embodiment 19)；

N, N- dimethyl -3- (4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 20)；

N, N- dimethyl -3- (4- (1- morpholinyl-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 21)；

N, N- dimethyl -3- (4- (1- (4- methylpiperazine-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 22)；

N, N- dimethyl -3- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 23)；

N, N- dimethyl -3- ((5- (1- morpholinyl-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 24)；

N, N- dimethyl -3- ((5- (1- (4- methylpiperazine-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 25)；

N, N- dimethyl -3- ((5- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 26)；

N, N- dimethyl -3- (4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 27)；

N, N- dimethyl -3- (4- (1- (1H- imidazoles -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 28)；

N, N- dimethyl -3- (4- (1- (1H- imidazol-4 yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 29)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine (embodiment 30)；

N, N- dimethyl -3- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 31)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 32)；

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 33)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine (embodiment 34)；

N, N- dimethyl -3- ((5- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine (embodiment 35)；

N, N- dimethyl -3- (4- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine (embodiment 36)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 37)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) H- pyrrolo- [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 38)；

8- phenyl -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 39)；

N, N, N- trimethyl -3- ((4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) amino) -1- propylamine salt (embodiment 40)；

1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 41)；

N- methyl-1-(4- (1- (tetrahydro-2H- pyrans-4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine (embodiment 42)；

N- ethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 43)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 44)；

N, N- dimethyl -1- (the chloro- 4- of 2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 45)；

N, N- dimethyl -1- (2- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 46)；

N, N- dimethyl -1- (2- trifluoromethyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 47)；

N, N- dimethyl -1- (the fluoro- 4- of 3- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 48)；

N, N- dimethyl -1- (the chloro- 4- of 3- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 49)；

N, N- dimethyl -1- (3- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 50)；

N, N- dimethyl -1- (3- trifluoromethyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 51)；

N, N- dimethyl -1- (6- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridin-3-yl) piperidines -4- amine (embodiment 52)；

N, N- dimethyl -1- (1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidin-4-yl) methylamine (embodiment 53)；

N, N- dimethyl -2- (1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidin-4-yl) -1- ethamine (embodiment 54)；

N, N- dimethyl -3- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 55)；

N, N- dimethyl -3- (the chloro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 56)；

N, N- dimethyl -3- (2- trifluoromethyl -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 57)；

N, N- dimethyl -1- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 58)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 59)；

N, N- dimethyl -1- (the chloro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 60)；

N, N- dimethyl -1- (2- trifluoromethyl -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 61)；

N, N- dimethyl -1- (the fluoro- 6- trifluoromethyl -4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 62)；

N, N- dimethyl -1- (the chloro- 6- trifluoromethyl -4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 63)；

N, N- dimethyl -1- (4- (1- (4- (dimethyl amido) piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 64)；

N, N- dimethyl -1- (4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 65)；

N- methyl-1-(4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine (embodiment 66)；

8- phenyl -1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine (embodiment 67)；

N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenyl) methylamine (embodiment 68)；

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine (embodiment 69)；

N- methyl-1-(4- (1- (tetrahydro-2H- pyrans-4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-8- base) phenyl) piperidines-4- amine (embodiment 70)；

N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenyl) piperidines -4- amine (embodiment 71)；

N, N- dimethyl -1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 72)；

1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 73)；

N- methyl-1-(4- (9- (tetrahydro-2H- pyrans-4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine (embodiment 74)；

N- ethyl -1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 75)；

N, N- dimethyl -1- (5- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) pyridine -2- base) piperidines -4- amine (embodiment 76)；

N- methyl-1-(4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) pyridine-2- base) piperidines-4- amine (embodiment 77)；

N, N- dimethyl -1- (4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 78)；

N, N- dimethyl -3- (4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 79)；

N, N- dimethyl -3- (4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 80)；

N, N- dimethyl -3- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 81)；

N, N- dimethyl -3- (the chloro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 82)；

N, N- dimethyl -3- (2- trifluoromethyl -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 83)；

N, N- dimethyl -1- (4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 84)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 85)；

N, N- dimethyl -1- (the chloro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 86)；

N, N- dimethyl -1- (2- trifluoromethyl -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 87)；

N, N- dimethyl -1- (fluoro- 6- trifluoromethyl -4- (the 9- ((3S of 2-, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 88)；

N, N- dimethyl -1- (chloro- 6- trifluoromethyl -4- (the 9- ((3S of 2-, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 89)；

N, N- dimethyl -1- (2- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine (embodiment 90)；

N, N- dimethyl -1- (2- (the fluoro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine (embodiment 91)；

N, N- dimethyl -1- (2- (the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine (embodiment 92)；

N, N- dimethyl -1- (2- (3- trifluoromethyl -4- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine (embodiment 93)；

N- methyl-1-(the fluoro- 4- of 2- (1- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine (embodiment 94)；

N- methyl-1-(2- (trifluoromethyl)-4- (1- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine (embodiment 95)；

N- ethyl -1- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 96)；

N- ethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 97)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 98)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -4- isopropyl -3,5- lupetazin -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 99)；

N, N- dimethyl -3- (the fluoro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 100)；

N, N- dimethyl -3- (the chloro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 101)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 102)；

N, N- dimethyl -1- (4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 103)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 104)；

N, N- dimethyl -1- (the chloro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 105)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 106)；

N- methyl-1-(2- (trifluoromethyl)-4- (1- ((2S, 6R)-2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine (embodiment 107)；

N- ethyl -1- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 108)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 109)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 110)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 111)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 112)；

N, N- dimethyl -1- (the chloro- 4- of 2- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 113)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 114)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((3R, 5S) -3,5- lupetidine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 115)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3R, 5S) -3,5- lupetidine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 116)；

N- methyl-1-(the fluoro- 4- of 2- (9- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine (embodiment 117)；

N- methyl-1-(2- (trifluoromethyl)-4- (9- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine (embodiment 118)；

N- ethyl -1- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 119)；

N- ethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 120)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 121)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -4- isopropyl -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 122)；

N, N- dimethyl -3- (4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 123)；

N, N- dimethyl -1- (4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 124)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 125)；

N, N- dimethyl -1- (the chloro- 4- of 2- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 126)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 127)；

N- methyl-1-(2- (trifluoromethyl)-4- (9- ((2S, 6R)-2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine (embodiment 128)；

N- ethyl -1- (2- (trifluoromethyl) -4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 129)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 130)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 131)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 132)；

N, N- dimethyl -1- (4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 133)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 134)；

N, N- dimethyl -1- (the chloro- 4- of 2- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 135)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 136)；

N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- ((3R, 5S) -3,5- lupetidine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 137)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3R, 5S) -3,5- lupetidine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 138)；

N, N- dimethyl -3- (the fluoro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 139)；

N, N- dimethyl -3- (the chloro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 140)；

N, N- dimethyl -3- (2- trifluoromethyl -4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine (embodiment 141)；

N, N- dimethyl -1- (the fluoro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 142)；

N, N- dimethyl -1- (the chloro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 143)；

N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 144)；

N, N- dimethyl -1- (the fluoro- 4- of 3- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine (embodiment 145)；

N, N- dimethyl -3- (the bromo- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 146)；

N, N- dimethyl -3- (the fluoro- 4- of 3- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 147)；

N, N- dimethyl -3- (2- fluoro- 6- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 148)；

N, N- dimethyl -3- (2- chloro- 6- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 149)；

N, N- dimethyl -3- (the fluoro- 4- of the chloro- 3- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 150)；

N, N- dimethyl -1- (the bromo- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine (embodiment 151)；

Or its officinal salt or prodrug.

" hydrogen (H) " used herein includes its isotope D and T.

" alkyl " used herein refers to that alkyl itself or linear chain or branched chain are up to the group of ten carbon atoms.Useful alkyl includes linear chain or branched chain C _1-10Alkyl, preferably C _1-6Alkyl, such as C _1-4Alkyl.Typical C _1-10Alkyl includes the methyl that can be arbitrarily replaced, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3- amyl, hexyl and octyl.

" alkenyl " used herein refers to that linear chain or branched chain contains 2-10 carbon atom, unless in addition carbon chain lengths are limited, it is wherein at least the group containing a double bond between two carbon atoms in chain.Typical alkenyl includes vinyl, 1- acrylic, 2- acrylic, 2- methyl-1-propylene base, 1- cyclobutenyl and 2- cyclobutenyl.

" alkynyl " used herein refers to that linear chain or branched chain contains 2-10 carbon atom, unless in addition carbon chain lengths are limited, it is wherein at least the group containing three key between two carbon atoms in chain.Typical alkynyl includes acetenyl, 1- propinyl, 1- methyl -2-propynyl, 2-propynyl, 1- butynyl and 2- butynyl.

Useful alkoxy includes by above-mentioned C _1-10The oxygroup that one of alkyl replaces, such as C _1-6Alkoxy or C _1-4Alkoxy.Alkyl in alkoxy can arbitrarily be replaced.It includes alkylamino and dialkylamino and carboxyl (including its ester group) that the substituent group of alkoxy, which includes but is not limited to halogen, morpholinyl, amino,.

Useful alkylthio group includes by above-mentioned C _1-10The sulfenyl that one of alkyl replaces, the alkyl in alkylthio group can arbitrarily be replaced.It simultaneously further include the sulfoxide and sulfone of this kind of alkylthio group.

Useful amino and the amino that can be arbitrarily replaced include-NR ₉R ₁₀, wherein R ₉And R ₁₀The C that is hydrogen or can arbitrarily be replaced _1-10Alkyl (such as C _1-6Alkyl or C _1-4Alkyl), naphthenic base, aryl, heteroaryl or amino.Or R ₉And R ₁₀5-8 element heterocycle such as piperidines or R are formed together with N ₉And R ₁₀5-8 element heterocycle such as piperazine is formed together with N and with other N or O.The alkyl and heterocycle can arbitrarily be replaced.

Useful halogen or halogen group includes fluorine, chlorine, bromine and iodine.

" aryl " used herein refers to aryl itself or a part as other groups, refers to the monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms.

Useful aryl includes C _6-14Aryl, preferably C _6-10Aryl.Typical C _6-14Aryl includes phenyl, naphthalene, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene and Fluorene base.

" heteroaryl " used herein refers to containing 5-14 annular atom, and has 6, and 10 or 14 pi-electrons share in ring system.And institute's ontaining annular atoms are carbon atom and optional 1-3 hetero atom from oxygen, nitrogen, sulphur.

Useful heteroaryl includes thienyl (thiophenyl), benzo [d] isothiazole -3- base, benzo [b] thienyl, naphtho- [2, 3-b] thienyl, thianthrene group, furyl, pyranose, isobenzofuran-base, chromene base, press from both sides xanthyl, thiophene dislikes base (phenoxanthiinyl), pyrrole radicals, imidazole radicals, pyrazolyl, pyridyl group, including but not limited to 2- pyridyl group, 3- pyridyl group and 4- pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, indolizine base, isoindolyl, 3H- indyl, indyl, indazolyl, purine radicals, 4H- quinazinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridines base, quinazolyl, cinnoline base, pteridyl, carbazyl, B-carboline base, phenanthridinyl, acridinyl, embedding phenodiazine (miscellaneous) phenyl of naphthalene, phenanthroline, azophenlyene Base, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazine base, 1,4- dihydro-quinoxaline -2,3- diketone, 7- amino isocoumarin, pyrido [1,2-a] pyrimidin-4-one, tetrahydro five member [c] pyrazole-3-yls, pyrazoles [1,5-a] pyrimidine radicals, pyrrolopyridinyl such as pyrroles [2,3-b] pyridyl group, benzo isoxazolyl such as 1,2- benzo isoxazole -3- base, benzimidazolyl, 2- hydroxyindole base, thiadiazole base and 2- oxobenzimidazolyl.When heteroaryl contains nitrogen-atoms in ring, such nitrogen-atoms can be in N- oxide form, such as pyridyl N-oxide, pyrazinyl N- oxide and pyrimidinyl N-oxide.

" carbocyclic ring (carbocylic radical) " used herein includes the carbon ring group of naphthenic base and fractional saturation.Useful naphthenic base is C _3-8Naphthenic base.Typical naphthenic base includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.

Useful saturation or fractional saturation carbon ring group is naphthenic base described above and cycloalkenyl, such as cyclopentenyl, cycloheptenyl and cyclo-octene base.

" heterocycle (heterocycle) " used herein refers to 3-7 person's monocycle of saturation or fractional saturation, or 7-10 person's bicyclic system, by carbon atom and from O, N, S, optional 1-4 hetero atom is formed for it, wherein hetero atom nitrogen and sulphur can be aoxidized arbitrarily, nitrogen can also be any quaternized, and merging including any heterocycle defined above in bicyclic system and phenyl ring.If the compound generated is to stablize, the carbon atom or nitrogen-atoms of heterocycle can be substituted.

Useful saturation or fractional saturation heterocyclic group includes tetrahydrofuran base, THP trtrahydropyranyl, pyranose, piperidyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, quininuclidinyl, morpholinyl, different Chromanyl, Chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl, these groups can arbitrarily be replaced.

Herein, when substituted, aryl, heteroaryl, carbocylic radical and heterocycle can be replaced by the substituent group that one or more (such as 1,2,3 or 4) is selected from following group: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C _1-6Acylamino-, C _1-6Acyloxy, C _1-6Alkoxy, aryloxy group, alkylthio group, C _1-6Alkyl, C _6-10Aryl, C _3-8Naphthenic base, C _2-6Alkenyl, C _2-6Alkynyl, C _6-10Aryl (C _2-6) alkenyl, C _6-10Aryl (C _2-6) alkynyl, saturation and unsaturated heterocycle or heteroaryl, methylenedioxy, C _1-6Halogenated alkyl, C _6-10Aryl (C _1-6) alkyl, C _1-6Hydroxyalkyl, urea groups, sulfydryl, azido, carbonyl, two (C _1-10Alkyl) amino, alkane sulfonyl, sulfamoyl, dialkyl sulfamine and alkyl sulphinyl etc..Wherein substituent group itself can also arbitrarily be replaced.

Herein, when substituted, alkyl, alkoxy, alkylthio group, alkenyl, alkynyl, naphthenic base, can be replaced by the substituent group that one or more (such as 1,2,3 or 4) are selected from following group: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C _1-6Acylamino-, C _1-6Acyloxy, C _1-6Alkoxy, aryloxy group, alkylthio group, C _1-6Alkyl, C _6-10Aryl, C _3-8Naphthenic base, C _2-6Alkenyl, C _2-6Alkynyl, C _6-10Aryl (C _2-6) alkenyl, C _6-10Aryl (C _{2- 6}) alkynyl, saturation and unsaturated heterocycle or heteroaryl, methylenedioxy, C _1-6Halogenated alkyl, C _6-10Aryl (C _1-6) alkyl, C _1-6Hydroxyalkyl, urea groups, sulfydryl, azido, carbonyl, two (C _1-10Alkyl) amino, alkane sulfonyl, sulfamoyl, dialkyl sulfamine and alkyl sulphinyl etc..Wherein substituent group itself can also arbitrarily be replaced.

In preferred embodiments, when substituted, alkyl, alkoxy, alkylthio group, alkenyl, alkynyl, naphthenic base, carbonyl, carbocyclic ring and heterocycle can be replaced by the substituent group that one or more (such as 1,2,3 or 4) is selected from following group: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C _1-6Acylamino-, C _1-6Acyloxy, C _1-6Alkoxy, aryloxy group, alkylthio group, C _1-6Alkyl, C _6-10Aryl, C _3-8Naphthenic base, C _2-6Alkenyl, C _2-6Alkynyl, C _6-10Aryl (C _2-6) alkenyl, C _6-10Aryl (C _2-6) alkynyl, saturation and unsaturated heterocycle or heteroaryl.

It should be understood that when as substituent group, the quantity of aryl or substituent group containing aryl, heteroaryl or substituent group containing heteroaryl, heterocycle or the substituent group containing heterocycle is usually 1.

" aryl alkyl " used herein includes by any above-mentioned C _6-14The C that aryl replaces _1-10Alkyl.Preferred aryl alkyl is benzyl, phenethyl or menaphthyl.

" aryl alkenyl " used herein includes by any above-mentioned C _6-14The C that aryl replaces _2-10Alkenyl.

" aromatic yl polysulfide yl " used herein includes by any above-mentioned C _6-14The C that aryl replaces _2-10Alkynyl.

" aryloxy group " used herein includes by any above-mentioned C _6-14The oxygroup that aryl replaces, aryl can arbitrarily be replaced.Useful aryloxy group includes phenoxy group and 4- methylphenoxy.

" alkoxy aryl " used herein includes the C replaced by any above-mentioned aryl _1-10Alkoxy, aryl can arbitrarily be replaced.Useful alkoxy aryl includes benzyloxy and phenyl ethoxy.

Useful halogenated alkyl includes the C replaced by one or more fluorine, chlorine, bromine or iodine atom _1-10Alkyl, preferably C _1-6Alkyl, such as methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 1,1- bis-fluoro ethyls, chloromethyl, chlorine methyl fluoride and trichloromethyl.

Useful acyl amino (acylamino-) is any C being connected on ammonia nitrogen _1-6Acyl group (alkanoyl), such as the C that acetylamino, chloro acetylamino, propionamido, butyrylamino, valeryl amino and hexanoyl amino and aryl replace _1-6Acyl amino, such as benzamido and pentafluoro benzoylamido.Useful acyl group includes C _1-6Acyl group, such as acetyl group.

Useful acyloxy is any C being connected on oxygen (- O-) _1-6Acyl group (alkanoyl), such as formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy, valeryl oxygroup and hexylyloxy.

It should be understood that containing A in compound of formula I ₁-A ₄Ring in, work as A ₁-A ₄Selected from the different atomic time, which contains A together with condensed with it ₁-A ₂Ring should meet bond-valence theory.Therefore, in some cases, when being selected from C or N, A ₁、A ₂、A ₃And A ₄It can be-CH- ,-N=,-NH- or-CH ₂-。

Moreover, it will be understood that can be from above-mentioned Formulas I, each A of II, IIIa and IIIb ₁-A ₄、B ₁-B ₃、D ₁-D ₄、R ₁-R ₁₀, R ', respectively select one or several groups in R " and R " ' limited range, combination forms preferred embodiment of the invention；And each technical characteristic in each embodiment of the present invention, each group definition and can be combined with each other between each technical characteristic specifically described in below (e.g. embodiment), to constitute preferred technical solution.For example, in certain embodiments, A ₁Preferably N；In certain embodiments, A ₂Preferably C；In certain embodiments, contain A ₁-A ₄Ring be preferably triazole ring, imidazole ring or pyrrole ring；In certain embodiments, B ₁For CR ", it is more preferred to B ₁For CH；In certain embodiments, B ₃For N；In certain embodiments, R ₃It is hydrogen.In certain embodiments, R ' is H；In certain embodiments, B ₁For CH, R ' and R ₃For H；In certain embodiments, A ₁For N, A ₂For C, B ₁For CH, R ' and R ₃For H；In certain embodiments, contain B ₁-B ₃Ring be phenyl ring or pyridine ring, preferably contain B ₁-B ₃Ring be phenyl ring or B ₃For the pyridine ring of N；In certain embodiments, contain A ₁And A ₂6 member rings be pyridine ring；In certain embodiments, contain A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, imidazo [1,5-c] quinazolyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl；In certain embodiments, R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle _1-6Alkyl；In certain embodiments, contain D ₁-D ₄Ring be can substituted pyridine ring, can substituted phenyl ring, can substituted pyrimidine ring or can substituted pyridine ring, preferably contain D ₁-D ₄Ring be can substituted phenyl ring；In certain embodiments, R ₂It is selected from: hydrogen ,-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NHR ₉, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl；In certain embodiments, R " ' is H, C _1-4Alkyl, halogen or halogenated C _1-4Alkyl.Each technical characteristic in above-mentioned each embodiment can any combination.Thus, for example, in certain embodiments, the compounds of this invention contains A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl, [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl, imidazo [1,5-c] quinazolyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl；Containing D ₁-D ₄Ring be can substituted pyridine ring, can substituted phenyl ring, can substituted pyrimidine ring or can substituted pyridine ring；R ', R " and R ₃For H；R " ' is H, C _1-4Alkyl, halogen or halogenated C _1-4Alkyl；R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle _1-6Alkyl；And R ₂It is selected from: hydrogen ,-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NHR ₉, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.

In certain embodiments, the compounds of this invention contains A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form [1,2,4] triazole simultaneously [4,3-a] quinoxalinyl；Containing D ₁-D ₄Ring be can be substituted including by R ₂Substituted pyridine ring, phenyl ring, pyrimidine ring or pyridine ring；R ', R " and R ₃For H；R " ' is H, C _1-4Alkyl, halogen or halogenated C _1-4Alkyl, preferably R " ' in D ₁And/or D ₂On position, or in D ₂And/or D ₃On position；R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, imidazole radicals, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by 1 heterocycle (preferably 1 morpholinyl) _1-6Alkyl；And R ₂It is selected from :-NR ₉R ₁₀, optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NH-, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl-NHR ₉, optionally by 1-3 C _1-4Alkyl-substituted piperazinyl, optionally by-NR ₉R ₁₀Substituted piperidyl and optionally by-NR ₉R ₁₀Substituted C _3-8Naphthenic base；Wherein, R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In these embodiments, preferred R ₁It is selected from:

Preferred R ₂It is selected from:

In these embodiments, more preferably R ₁It is selected from:

More preferably R ₂It is selected from:

In certain embodiments, the compounds of this invention contains A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl and pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl；Containing D ₁-D ₄Ring be pyridine ring or phenyl ring；R ', R ", R " ' and R ₃For H；R ₁Selected from THP trtrahydropyranyl；And R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, optionally by-NR ₉R ₁₀Substituted C _1-6Alkyl and optionally by-NR ₉R ₁₀Substituted piperidyl, wherein R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In certain embodiments, the compounds of this invention contains A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form imidazo [1,5-c] quinazolyl, imidazo [1,5-a] quinoxalinyl, imidazo [1,2-a] quinoxalinyl or pyrrolo- [1,2-a] quinoxalinyl；Containing D ₁-D ₄Ring be pyridine ring or phenyl ring；R ', R ", R " ' and R ₃For H；R ₁Selected from THP trtrahydropyranyl and morpholinyl；And R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy, wherein R ₉And R ₁₀It is independently selected from C _1-6Alkyl.In these embodiments, preferred R ₁And R ₂It can be as described in any embodiment above.

In embodiment, the compounds of this invention contains A ₁-A ₄Ring, contain A ₁-A ₂6 member rings with contain B ₁-B ₃Ring condensed form pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazinyl；Containing D ₁-D ₄Ring be pyridine ring or phenyl ring, preferably phenyl ring；R ', R " and R ₃For H；R " ' is H, C _1-4Alkyl, halogen or halogenated C _1-4Alkyl, preferably H, halogen or halogenated C _1-4Alkyl, preferably R " ' in D ₁And/or D ₂On position or in D ₂And/or D ₃On position；R ₁Selected from unsubstituted or optionally by 1-4 C _1-6It is alkyl-substituted THP trtrahydropyranyl, unsubstituted or optionally by-NR ₉R ₁₀Or 1-4 C _1-6It is alkyl-substituted piperidyl, unsubstituted or optionally by 1-4 C _1-6Alkyl-substituted morpholinyl, optionally by 1-4 C _1-6Alkyl-substituted piperazinyl or the C optionally replaced by heterocycle _1-6Alkyl；And R ₂Selected from optionally by-NR ₉R ₁₀Substituted C _1-6Alkoxy and optionally by-NR ₉R ₁₀Substituted piperidyl, wherein R ₉And R ₁₀It is independently selected from hydrogen or C _1-6Alkyl.In these embodiments, preferred R ₁It is selected from:

Preferred R ₂It is selected from:

Moreover, it will be understood that in Formulas I of the invention, Formula II, formula III a and formula III b, A ₁-A ₄、B ₁-B ₃And D ₁-D ₄Selection should meet valence bond theory.Thus, for example, in some cases, to meet valence bond theory, when unsubstituted, the C on ring can be CH or CH ₂Or N can be NH.

Some the compounds of this invention may be used as stereoisomer, including optical isomer to exist.The present invention includes the racemic mixture of all stereoisomers and such stereoisomer, and the individual enantiomer that can be separated according to method well known to the skilled person.

The example of officinal salt includes inorganic and acylate, such as hydrochloride, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates；And the inorganic and organic alkali salt formed with alkali such as sodium hydroxyl, three (hydroxymethyl) aminomethanes (TRIS, tromethamine) and N-METHYL-ALPHA-L-GLUCOSAMINE.

The embodiment of the prodrug of the compounds of this invention include the compound containing carboxylic acid simple ester (such as according to means known in the art by with C _1-4The ester of alcohol condensation and acquisition)；Compound containing hydroxyl ester (such as according to means known in the art by with C _1-4Carboxylic acid, C _3-6Diacid or the ester of the condensation of its acid anhydrides such as succinic anhydride and fumaric acid anhydride and acquisition)；Compound containing amino imines (such as according to means known in the art by with C _1-4The imines of aldehydes or ketones condensation and acquisition)；Those of carbamate, such as Leu of compound containing amino et al. (J.Med.Chem.1999,42:3623-3628) and Greenwald et al. (J.Med.Chem.1999,42:3657-3667) description ester；The acetal or ketal (such as foundation means known in the art those of acquisition acetal and with Chloromethyl methyl ether or chloromethyl ethyl ether condensation) of compound containing alcohol.

Method known to those skilled in the art or new method of the present invention can be used to be made for the compounds of this invention.Specifically, there is Formulas I, the compounds of this invention of Formula II or formula III can be made as shown in the reaction embodiment in reaction scheme 1.50% toluene solution of 2,3- diamino -5- bromopyridines and glyoxylic acid ethyl ester, which is mixed in dioxane, heats reaction, obtains product 2- hydroxyl -7- bromopyridine simultaneously [2,3-b] pyrazine.Simultaneously [2,3-b] pyrazine is dissolved in phosphorus oxychloride heating reaction to 2- hydroxyl -7- bromopyridine, obtains the chloro- 7- bromopyridine of product 2- simultaneously [2,3-b] pyrazine.Simultaneously [2,3-b] pyrazine and hydrazine hydrate heat reaction to the chloro- 7- bromopyridine of 2- in ethanol, obtain product 2- diazanyl -7- bromopyridine simultaneously [2,3-b] pyrazine.2- diazanyl -7- bromopyridine simultaneously [2,3-b] pyrazine and oxinane -4- formaldehyde reacts at room temperature in methyl alcohol, obtained intermediate product and iodobenzene acetate reacts at room temperature in methylene chloride, obtain the bromo- 1- of product 8- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine.The bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) pyrido [2, 3-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine, (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid, cesium carbonate and [1, 1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex heat reaction in dioxane and water, obtain target compound N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2, 3-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -8- base) pyridine -2- base) oxygroup) -1- propylamine.

Reaction scheme 1

Other related compounds can be made with similar approach.Such as, with N, N- dimethyl -3- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) phenoxy group) -1- propylamine substitution (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid, target compound N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2 can be made, 3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine.With 3,4- diamino -6- bromopyridine substitution 2,3- diamino -5- bromopyridine, target compound N can be made, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine.

The compounds of this invention can be made as shown in the reaction embodiment in reaction scheme 2.2- hydroxy quinoxaline and bromine react at room temperature in acetic acid, obtain product 2- hydroxyl -7- bromine quinoxaline.2- hydroxyl -7- bromine quinoxaline is dissolved in phosphorus oxychloride, and reaction is heated under the catalysis of DMF, obtains the chloro- 7- bromine quinoxaline of product 2-.The chloro- 7- bromine quinoxaline of 2- and hydrazine hydrate heat reaction in ethanol, obtain target product 2- diazanyl -7- bromine quinoxaline.2- diazanyl -7- bromine quinoxaline and oxinane -4- formaldehyde react at room temperature in methyl alcohol, obtained intermediate product and iodobenzene acetate reacts at room temperature in methylene chloride, obtains the bromo- 1- of product 8- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.The bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline, (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid, cesium carbonate and [1, 1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex heat reaction in dioxane and water, obtain target compound N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine.

Reaction scheme 2

Other related compounds can be made with similar approach.For example, with N, N- dimethyl -3- (4- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) phenoxy group) -1- propylamine substitution (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid, target compound N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2 can be made, 4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.Oxinane -4- formaldehyde is substituted with morpholine -4- formaldehyde, can be made target compound N, N- dimethyl -3- (4- (1- morpholinyl-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.With (2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- phosgene substitutes oxinane -4- formaldehyde, target compound N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2R, 6S) -2 can be made, 6- dimethyl tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.Oxinane -4- formaldehyde is substituted with 4- (dimethylamino) piperidines -1- phosgene, target compound N can be made, N- dimethyl -1- (4- (1- (4- (dimethyl amido) piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.With (2R, 6S) -2,6- thebaine -4- phosgene substitutes oxinane -4- formaldehyde, target compound N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2 can be made, 6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.With N, N- dimethyl -1- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) phenyl) piperidines -4- amine substitution (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid, target compound N, N- dimethyl -1- (4- (1- ((2S, 6R) -2 can be made, 6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.Oxinane -4- formaldehyde is substituted with piperidines -1- phosgene, target compound N can be made, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.With (3S, 5R) -3,5- lupetidine -1- phosgene substitutes oxinane -4- formaldehyde, target compound N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3R, 5S) -3 can be made, 5- lupetidine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.

The compounds of this invention can be made as shown in the reaction embodiment in reaction scheme 3.The bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazol [4,3-a] quinoxaline and connection boric acid pinacol ester be in potassium acetate and [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride catalysis under conditions of in dioxane heat reaction, obtain product 1- (tetrahydro -2H- pyrans -4- base) -8- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.1- (tetrahydro -2H- pyrans -4- base) -8- (4, 4, 5, 5- tetramethyl -1, 3, penta ring -2- base of 2- dioxy boron)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline and N, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine is in cesium carbonate and [1, 1 '-bis- (diphenylphosphino) ferrocene] palladium chloride catalysis under conditions of the in the mixed solvent of dioxane and water heat react, obtain target compound N, N- dimethyl -3- ((6- (1- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) pyridin-3-yl) oxygroup) -1- propylamine.

Reaction scheme 3

Other related compounds can be made with similar approach.Such as, with 1- (4- bromophenyl)-N, N- lupetidine -4- amine substitutes N, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine, target compound N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2 can be made, 4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.N is substituted with 1- (4- bromophenyl) -4- methyl piperazine, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine, target compound 8- (4- (4- methylpiperazine-1-yl) phenyl) -1- (tetrahydro -2H- pyrans -4- base)-[1 can be made, 2,4] triazole simultaneously [4,3-a] quinoxaline.Use N ¹(4- bromophenyl)-N ³, N ³Dimethyl propylene -1,3- diamines substitutes N, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine, target compound N- (3- (dimethylamino) propyl) -4- (1- (tetrahydro -2H- pyrans -4- base)-[1 can be made, 2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) aniline.N is substituted with 4- ((4- (dimethylamino) cyclohexyl) phenyl) triflate, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine, target compound N can be made, N- dimethyl -4- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) cyclohexylamine.

The compounds of this invention can be made as shown in the reaction embodiment in reaction scheme 4.(2R, 6S) -2,6-dimethyl-piperizine -1- t-butyl carbonate and triphosgene react at room temperature in methylene chloride and pyridine, obtain product (2R, 6S) -4- (chloroformyl) -2,6-dimethyl-piperizine -1- t-butyl carbonate.(2R; 6S) -4- (chloroformyl) -2; the dichloromethane solution of 6- lupetazin -1- t-butyl carbonate and the bromo- 2- diazanyl quinoxaline of 7- is in N; it is reacted at room temperature in N- diisopropylethylamine; obtain product (2R; 6S) -4- (2- (7- bromine quinoxaline -2- base) hydrazine -1- formoxyl) -2,6-dimethyl-piperizine -1- t-butyl carbonate.(2R; 6S) -4- (2- (7- bromine quinoxaline -2- base) hydrazine -1- formoxyl) -2; 6- lupetazin -1- t-butyl carbonate heats reaction in phosphorus oxychloride; obtain bromo- the 1- ((2R of product 8-; 6S) -3,5- lupetazin -1- base)-[1,2; 4] triazole simultaneously [4,3-a] quinoxaline.The bromo- 1- of 8- ((2R, 6S) -3,5- lupetazin -1- base)-[1,2,4] simultaneously [4,3-a] quinoxaline, formic acid and 40% formalin heat reaction to triazole in methyl alcohol, obtain bromo- the 1- ((2R of product 8-, 6S) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.Bromo- the 1- ((2R of 8-, 6S) -3, 4, 5- tri methyl piperazine -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline and 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester is [1, 1 '-bis- (diphenylphosphino) ferrocene] palladium chloride and cesium carbonate catalysis under reaction is heated in dioxane and water, obtain target compound N, N- dimethyl -3- (4- (1- ((2R, 6S) -3, 4, 5- tri methyl piperazine -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.

Reaction scheme 4

Other related compounds can be made with similar approach.Such as, with N, N- dimethyl -1- (4- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) phenyl) piperidines -4- amine substitution 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester, target compound N, N- dimethyl -1- (4- (1- ((3S can be made, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.With 3- diazanyl -6- chloropyridine simultaneously [2,3-b] the pyrazine substitution bromo- 2- diazanyl quinoxaline of 7-, target compound N, N- dimethyl -3- (4- (9- ((3S, 5R) -3 can be made, 4,5- tri methyl piperazine -1- base) pyrido [3,2- e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine.With N, N- dimethyl -1- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) -2- (trifluoromethyl)-phenyl) piperidines -4- amine substitution 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester, target compound N, N- dimethyl -1- (2- trifluoromethyl -4- (9- ((3S, 5R) -3 can be made, 4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine.Formalin is substituted with iodoethane, target compound N can be made, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] piperazine -2- base) phenyl) piperidines -4- amine.

The compounds of this invention can be made as shown in the reaction embodiment in reaction scheme 5.6- chloropyridine simultaneously [2,3-b] (4H) -one of pyrazine -3 and hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, N, N- diisopropylethylamine is in N, it is reacted at room temperature in dinethylformamide, it is then added at 0 DEG C of hydrazine hydrate and reacts, obtain product 3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine.3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine and oxinane -4- formaldehyde reacts at room temperature in methanol, obtain the chloro- 3- of product 6- (2- ((tetrahydro -2H- pyrans -4- base) methylene) diazanyl) pyrido [2,3-b] pyrazine.The midbody product and iodobenzene acetate react at room temperature in methylene chloride, obtain the chloro- 9- of product 2- (tetrahydro -2H- pyrans -4- base) pyridine [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine.The chloro- 9- of 2- (tetrahydro -2H- pyrans -4- base) pyridine [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine and 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester under the catalysis of cesium carbonate and tetrakis triphenylphosphine palladium the in the mixed solvent of dioxane and water heat react, obtain target compound N, N- dimethyl -3- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine.

Reaction scheme 5

Other related compounds can be made with similar approach.For example, with N, N- dimethyl -1- (4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron, penta ring -2- base) phenyl) piperidines -4- amine substitution 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester, target compound N can be made, N- dimethyl -1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine.Oxinane -4- formaldehyde is substituted with 2- morpholine acetaldehyde, target compound N, N- dimethyl -3- (4- (9- (morpholinyl methyl) pyrido [3 can be made, 2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine.Oxinane -4- formaldehyde is substituted with 4- (dimethylamino) piperidines -1- phosgene, target compound N can be made, N- dimethyl -1- (2- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine.With (2R, 6S) -2,6- thebaine -4- phosgene substitutes oxinane -4- formaldehyde, and target compound N, N- dimethyl -1- (4- (9- ((2S can be made, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine.With (2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- phosgene substitutes oxinane -4- formaldehyde, and target compound N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((2R can be made, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine.Oxinane -4- formaldehyde is substituted with piperidines -1- phosgene, target compound N can be made, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine.With (3S, 5R) -3,5- lupetidine -1- phosgene substitutes oxinane -4- formaldehyde, and target compound N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- ((3R can be made, 5S) -3,5- lupetidine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine.

An importance of the invention is to have found Formulas I, and the compound of Formula II and formula III is kinase inhibitor, especially ATM kinase inhibitor.Therefore, these compounds can be used to treat or prevent a variety of because clinical disease or benefiting from the repressed disease of kinase activity, such as cancer caused by DDR functional defect.In certain embodiments, the disease that the compounds of this invention, Pharmaceutical composition or method can be used to treat or prevent is DDR mediation or kinase mediated disease, cancer as described below.

The invention also includes apply a effective amount of Formulas I, the treatment or prevention method of Formula II or formula III compound or pharmaceutically acceptable salt thereof or prodrug to animal.Wherein the treatment or prevention method is for treating or preventing because of clinical disease caused by DDR functional defect or benefiting from the repressed disease of kinase activity or DDR mediation or kinase mediated disease, such as cancer.This kind of disease includes but is not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin lymphoma, acute lymphatic leukaemia, chronic lymphocytic leukemia, Huppert's disease, neuroblastoma, breast cancer, oophoroma, lung cancer, wilms' tumor, cervix cancer, carcinoma of testis, soft tissue sarcoma, primary macroglobulinaemia, bladder cancer, chronic myelocytic leukemia, primary brain cancer, chromoma, Small Cell Lung Cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid carcinomas, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, cancer of pancreas, acute myeloblastic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi sarcoma, urogenital neoplasm disease, thyroid cancer, the cancer of the esophagus, malignant hypercalcemia, hyperplasia of cervix uteri disease, clear-cell carcinoma, carcinoma of endometrium, true property is red Cytosis, essential thrombocythemia, adrenocortical carcinoma, cutaneum carcinoma and prostate cancer.

When implementing subject treatment method, a effective amount of pharmaceutical preparation is applied to the patient for there are these one or more symptoms.The pharmaceutical preparation contains the Formulas I of effective treatment concentration, Formula II or formula III compound, is formulated for taking orally, be injected intravenously, the form of part or topical administration, being used for treating cancer and other diseases.Dosage is the dose for effectively improving or eliminating one or more illnesss.Treatment for specified disease, effective quantity are the doses for being enough to improve or mitigate in some manner symptom related with disease.Such dose can be used as single dose application, or can be administered according to effective therapeutic scheme.Dosage also permits to cure disease, but is administered typically to the symptom for improving disease.Repetitively administered is generally required to realize that required symptom improves.

A kind of Pharmaceutical composition is provided in another embodiment, wherein containing the Formulas I of kinase inhibitor or its officinal salt and pharmaceutical acceptable carrier.

Another embodiment of the invention is related to capable of effectively treating or the Pharmaceutical composition of pre- anti-cancer, it wherein include the Formulas I of kinase inhibitor, Formula II or formula III compound or its officinal salt or prodrug are combined with the officinal salt of at least one known anticancer drug or anticancer drug and are shared.It is especially shared with combining for other anticancer drugs related with DNA damage and repair mechanisms, including PARP inhibitor olaparib, Niraparib, Rucaparib and Talazoparib；Hdac inhibitor Vorinostat, sieve miaow pungent, pabishta and Baily department he；Etc..And it is shared with combining for other anticancer drugs related with cell division test point, including Chk1/2 inhibitor, CDK4/6 inhibitor such as Pa Boxini, Wee1/ATR inhibitor etc..The known anticancer drugs that can be used for anti-cancer combination treatment include but is not limited to alkylating agent such as busulfan, cis-platinum, mitomycin C and carboplatin；Antimitotic agent such as colchicin, vincaleukoblastinum, Japanese yew be liquor-saturated and docetaxel；Topoisomerase I preparation such as camptothecine and topotecan；Topoisomerase II inhibitors such as adriamycin and etoposide；RNA/DNA antimetabolite such as 5-azacitidine, 5 FU 5 fluorouracil and methotrexate (MTX)；The fluoro- 2 '-uracil deoxyriboside of DNA antimetabolite such as 5-, cytarabine, hydroxycarbamide and thioguanine；Antibody such as monoclonal antibody, Trastuzumab and Mabthera.Other known anticancer drugs that can be used for anti-cancer combination treatment include melphalan, Chlorambucil, cyclophosphamide, ifosfamide, vincristine, mitoguazone, Epi-ADM, aclacinomycin, bleomycin, mitoxantrone, methyl hydroxy ellipticine, fludarabine, Octreotide, retinoic acid, tamoxifen, arsenic, gemcitabine, Letrozole, fulvestrant, bendamustine, Pralatrexate, pemetrexed, nelarabine, Temozolomide, zoledronic acid, Irinotecan, Ipsapirone, Cabazitaxel, vinorelbine, Victibix, Ofatumumab, Avastin, Imatinib, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sutent, nilotinib, Dasatinib, pazopanib, bortezomib, Vorinostat, sieve miaow ester peptide, special cancer is suitable, everolimus, Sa Li polyamines, lenalidomide and the cry of certain animals of sulphur bird throat.

When implementing method of the invention, the compounds of this invention at least one known anticancer drug can be used as single Pharmaceutical composition together be administered.In addition, the compounds of this invention can also separately be administered with anticarcinogen known at least one.In an embodiment, anticarcinogen known to the compounds of this invention and at least one is almost administered simultaneously, i.e., all drugs are administered simultaneously or apply successively, as long as compound reaches treatment concentration simultaneously in blood.In another embodiment, anticarcinogen known to the compound of the present invention and at least one is according to respective dose regimen, as long as compound reaches treatment concentration in blood.

Another embodiment of the invention, be it is a kind of can effectively inhibit tumour by what the compound formed, the biological coupling object as kinase inhibitor.This can inhibit the biological coupling object of tumour by the compound and at least one known antibody for having medical function, such as Trastuzumab or Mabthera or auxin, such as DGF or NGF, or cytohormone, such as interleukin 2 or 4, or arbitrarily can be with the molecular composition in conjunction with cell surface.The compound can be delivered to its target spot by the antibody and other molecules, make effective anticancer drug.This biological coupling object can also be improved the antibody of medical function, such as Trastuzumab or the anticancer effect of Mabthera.

Another embodiment of the present invention be related to a kind of Pharmaceutical composition that can effectively inhibit tumour, the Formulas I comprising kinase inhibitor, Formula II or formula III compound or its can medication salt or prodrug, with radiotherapy combination therapy.In this embodiment, the compounds of this invention and radiotherapy can be administered in same time or different time.

Another embodiment of the present invention is related to a kind of Pharmaceutical composition that can be effectively used for treating after cancer operation, the Formulas I comprising kinase inhibitor, Formula II or formula III compound or it can medication salt or prodrug.The invention further relates to ocal resection, the treatment method of the cancer of the mammal is then treated with Pharmaceutical composition of the invention.

Pharmaceutical composition of the invention includes that the amount of all the compounds of this invention can effectively realize the medicine preparation of its target.Although each Man's Demands are different, those skilled in the art can determine the optimal dose of each part in medicine preparation.Under normal circumstances, the compound or its can medication salt, mammal is administered orally daily, dose is according to about 0.0025 to 50 mg kg of body weights.It is preferred that per kilogram is administered orally about 0.01 to 10 mgs/kg.If also applying a known anticancer drug, dosage should can effectively realize its expected purpose.The optimal dose of these known anticancer drugs is well-known to those skilled in the art.

Unit oral doses may include about 0.01 to 50 milligrams, preferably about 0.1 to 10 milligrams of the compounds of this invention.Unit dose can be given one or many, be daily one or more pieces, and every contains about 0.1 to 50 milligrams, eligibly about 0.25 to 10 milligrams of the compounds of this invention or its solvate.

In external preparation, the concentration of the compounds of this invention can be about 0.01 to 100 milligrams of every gram of carrier.

The compounds of this invention can be used as undressed drug products for administration.The compounds of this invention can also be used as a part administration of a suitable pharmaceutical preparation containing pharmaceutical acceptable carrier (including auxiliary material and auxiliary agent).These pharmaceutical acceptable carrier are conducive to compound is processed into pharmaceutical pharmaceutical preparation.Preferred pharmaceutical preparation, especially those oral and preferred administration mode types, such as tablet, pastille and capsule, and be suitable for injecting or oral solution, include about 0.01% to 99%, preferably from about 0.25% to 75% reactive compound and auxiliary material.

The scope of the present invention also includes the non-toxic officinal salt of the compounds of this invention.Acid-addition salts are formed by mixing one non-toxic pharmaceutically acceptable acid solution and the compound of the present invention solution.The acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid etc..Base addition salts are formed by the pharmaceutically acceptable aqueous slkali of one nontoxicity of mixing and the compound of the present invention solution.The alkali such as sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, trishydroxymethylaminomethane, N- methyl-glucamine etc..

Pharmaceutical preparation of the invention can give any mammal, as long as they can obtain the therapeutic effect of the compounds of this invention.The most importantly mankind and veterinary animal in these mammals, although the present invention be not intended to it is so limited.

Pharmaceutical preparation of the invention can be administered by any approach to reach its expected purpose.For example, can be by parenteral, subcutaneously, vein, muscle is intraperitoneal, transdermal, oral cavity, intrathecal, encephalic, nasal cavity or topical route administration.As substitution or concurrently, can be administered orally.The dosage of medicine will be determined according to the age of patient, health and weight, the type of concurrent treatment, the frequency for the treatment of and required treatment benefit.

Pharmaceutical preparation of the invention can manufacture in a known manner.For example, granulation, ingot processed, dissolution or freezing dry process manufacture by traditional mixing.When manufacturing oral preparation, in combination with solid adjuvant material and reactive compound, selective milled mixtures.After if necessary or appropriate amount of addition agent being added when necessary, granulate mixture is processed, obtains tablet or pastille core.

Suitable auxiliary material especially filler, such as carbohydrate such as lactose or sucrose, mannitol or sorbierite；Cellulose preparation and/or calcium phosphate, such as tricalcium phosphate or calcium monohydrogen phosphate；And binder, such as gelatinized corn starch, including cornstarch, wheaten starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone.If desired, disintegrating agent can be increased, than starch as mentioned above and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.Adjuvant especially flowing regulator and lubricant, for example, silica, talcum, stearic acid or its salt, such as magnesium stearate or calcium stearate and/or polyethylene glycol.If desired, the suitable coating that can resist gastric juice can be provided to pastille core.For this purpose, can be using concentration saccharide solution.This solution can contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture.In order to prepare the coating of resistant to gastric juice, cellulose solution appropriate, such as cellulose acetate phthalic acid or hydroxypropyl methyl cellulose phthalic acid can be used.Dyestuff or pigment can be added to the coating of tablet or pastille core.For example, for identification or in order to characterize the combination of active constituent dosage.

Other orally available pharmaceutical preparations include compression joint type capsule made of gelatin, and soft capsule is sealed made of the plasticizer such as gelatin and glycerol or sorbierite.The reactive compound of the compression joint type capsule containing particle form, with filler such as lactose；Binder such as starch；And/or lubricant such as talcum powder or magnesium stearate and stabilizer mix.In soft capsule, reactive compound is preferably dissolved or suspended in liquid appropriate such as grease or atoleine, wherein stabilizer can be added.

The preparation for being appropriate to parenteral administration includes the aqueous solution of reactive compound, such as the solution and alkaline solution of water soluble salt.In addition, the oily injection suspensions of reactive compound appropriate can be applied.Suitable lipophilic solvent or carrier include grease such as sesame oil, Acrawax such as ethyl oleate or triglycerides or polyethylene glycol 400 or rilanit special or cyclodextrin.Water injection suspension liquid contains the substance for increasing suspension viscosity, such as sodium carboxymethylcellulose, sorbierite and/or glucan.Suspension stabilizer can also be contained.

According to one aspect of the present invention, the compound of the present invention uses external application and parenteral formulation, and for treating cutaneum carcinoma.

Finish, creme, emulsion agent, ointment etc. can be made by preferred suitable carrier in external preparation of the invention.Suitable carrier includes plant or mineral oil, and White Mineral Oil (paraffinum molle alba), Branched fatty or grease, animal tallow and high molecular alcohol (are greater than C ₁₂).Preferred carrier is that active constituent can be dissolved in those of wherein carrier.It may also comprise emulsifier, stabilizer, moisturizer and antioxidant, and if necessary, give the reagent of color or fragrance.In addition, these external preparations may include dermal penetration enhancers.The example of this reinforcing agent can be found in U.S. Patent number 3,989,816 and 4,444,762.

Creme preferably uses mineral oil, and the mixture preparation of self emulsifying beeswax and water is mixed with the active constituent for being dissolved in a small amount of oily such as apricot kernel oil.One typical creme example includes about 40 parts of water, 20 parts of beeswaxs, 40 parts of mineral oil and 1 portion of apricot kernel oil.

Ointment can be prepared in this way, and the soft paraffin of the vegetable oil containing active constituent such as apricot kernel oil and warm is mixed, and then make the mixture cooling.One typical ointment example includes the apricot kernel oil of about 30% weight and the paraffinum molle alba of 70% weight.

The following example is for example, rather than limiting method and formulation of the invention.Other it will become apparent to those skilled in the art that and would ordinarily be encountered in clinical treatment to the suitably modified of various conditions and parameter and improve, would be within the spirit and scope of the present invention.

Embodiment

General explanation

Agents useful for same is marketing quality, and solvent is purified according to standard method is dry.Mass spectrum sample is analyzed using single level four bars mass spectrograph (platform II, Agilent 6110) of electron spray.It is recorded using 400 nuclear magnetic resonance spectrometer of Br ü cker Ascend in 400MHz ¹H NMR spectra, chemical shift are recorded as beginning as unit of ppm using TMS as internal standard (0.00ppm) from low field, and coupling constant J value is as unit of Hz.In addition to the intermediate synthesis that each embodiment specifically describes, the synthesis of moiety intermediate is hereafter also given, except following mentioned methods, other intermediate substituted aryls can also be synthesized by known method by those skilled in the art and are made.

Intermediate: the synthesis of substituted aryl

1) 4- (4- ((dimethylamino) cyclohexyl) phenyl) triflate

A) 4- ((dimethylamino) hexamethylene -1- alkene -1- base) triflate: by 4- dimethylamino cyclohexanone (500mg, it 3.54mmol) is dissolved in anhydrous tetrahydro furan (10mL), bis- (fluoroform sulphonyl) imines (1.39g, 3.9mmol) of N- phenyl are added.Nitrogen is replaced three times, and after reaction system is cooled to -78 DEG C, double methylsilyl lithium amides (4.3mL, 4.25mmol) are slowly added dropwise.After being added dropwise, it is warmed to room temperature and reaction is stirred at room temperature overnight.Ethyl acetate (20mL) is added into reaction solution and water (5mL) extracts liquid separation, water phase is extracted with ethyl acetate (10mL × 2), merge organic phase, it is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, filtering, is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (630mg, 65% yield, light yellow oil).LC-MS (ESI): m/z (M+1) 274.07.

B) N, N- dimethyl -4 '-methoxyl group -2,3,4,5- tetrahydro-[1,1 '-biphenyl] -4- amine: at room temperature, by 4- ((dimethylamino) hexamethylene -1- alkene -1- base) triflate (625mg, 2.3mmol), 4- methoxyphenylboronic acid (524mg, 3.45mmol), potassium acetate (677mg, the in the mixed solvent of dioxane (4mL) and water (1mL) 6.9mmol) is dissolved in [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (188mg, 0.23mmol).Nitrogen is replaced 3 times, after reaction mixture is stirred to react 1h at 10 DEG C, is cooled to room temperature.Filtering, is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (230mg, 43.47% yield, colorless oil).LC-MS (ESI): m/z (M+1) 232.17.

C) N, N- dimethyl -4- (4- methoxyphenyl) cyclohexyl -1- amine: at room temperature, by N, N- dimethyl -4 '-methoxyl group -2,3,4,5- tetrahydro-[1,1 '-biphenyl] -4- amine (230mg, 0.99mmol) is dissolved in ethyl alcohol (10mL), it is added palladium carbon (23mg, w/w=10%).Hydrogen is replaced three times, and reaction is stirred at room temperature under an atmosphere of hydrogen overnight.Filtering, is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (212mg, 91.38% yield, brown solid).LC-MS (ESI): m/z (M+1) 232.17.

D) 4- (4- (dimethylamino) cyclohexyl) phenol: at room temperature, by N, N- dimethyl -4- (4- methoxyphenyl)-cyclohexyl -1- amine (212mg, it 0.92mmol) is dissolved in anhydrous methylene chloride (10mL), Boron tribromide (115 μ L are added dropwise under ice-water bath, 2.76mmol), it is warmed to room temperature after being added dropwise, and reaction 1h is stirred at room temperature.Add water (5mL) quenching reaction.Methylene chloride (20mL) is added and extracts liquid separation, water phase is extracted with methylene chloride (10mL × 2), is merged organic phase, is washed with saturated salt solution (15mL), and anhydrous sodium sulfate is dry, is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (130mg, 65.24% yield, weak yellow liquid).LC-MS (ESI): m/z (M+1) 220.17.

E) 4- (4- ((dimethylamino) cyclohexyl) phenyl) triflate: at room temperature, by 4- (4- (dimethylamino) cyclohexyl) phenol (130mg, it 0.6mmol) is dissolved in methylene chloride (4mL), bis- (fluoroform sulphonyl) imines (322mg of N- phenyl are added, 0.9mmol), 4-dimethylaminopyridine (7mg, 0.06mmol) and triethylamine (126 μ L, 1.16mmol).Reaction 3h is stirred at room temperature in reaction mixture.It is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (170mg, 81.62% yield, weak yellow liquid).LC-MS (ESI): m/z (M+1) 352.11.

2) N, N- dimethyl -1- (the bromo- 2- fluorophenyl of 4-) piperidines -4- amine

At room temperature, by the bromo- 2- fluorine iodobenzene (700mg, 2.33mmol) of 4-, N, N- dimethylaminopyridine (359mg, 2.80mmol), tris(dibenzylideneacetone) dipalladium (213mg, 0.23mmol), 4,5- bis- diphenylphosphine -9,9- xanthphos (270mg, 0.47mmol) it is added in dioxane (15mL) with cesium carbonate (1.89g, 5.83mmol).After reaction system is replaced 3 times with nitrogen, it is stirred to react at 100 DEG C overnight.It is cooled to room temperature, filters, removing organic solvent is concentrated under reduced pressure and obtains crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=15: 1 is eluant, eluent) obtains target compound (350mg, 49% yield, yellow liquid).LC-MS (ESI): m/z (M+1) 301.32.

Other N, N- dimethyl -1- (the bromo- substituted-phenyl of 4-) piperidines -4- amine can be using similar synthetic intermediate 2) method be made, starting material N, N- dimethylaminopyridine and the bromo- substitution iodobenzene of corresponding 4-.

3) N, N- dimethyl -1- (1- (4- bromophenyl) piperidin-4-yl) methylamine

A) 4- (methylol) piperidines -1- t-butyl formate: by 1- (tert-butoxycarbonyl) piperidines -4- formic acid (5.0g; it 22mmol) is dissolved in anhydrous tetrahydro furan (80mL); after being cooled to 0 DEG C; borine tetrahydrofuran solution (1M is added under nitrogen protection; 33mL, 33mmol).After being added dropwise, reaction mixture stirs 2 hours at 0 DEG C.Hydrochloric acid solution (1M, 33mL, 33mmol) is slowly added dropwise.It after reaction mixture stirs 30min at 0 DEG C, is added methylene chloride (100mL), separates organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give target compound (3.8g, 80% yield, colorless oil).LC-MS (ESI): m/z (M+1) 216.16.

B) 4- ((benzoyloxy) methyl) piperidines -1- carboxylic acid tert-butyl ester: at room temperature, by 4- (methylol) piperidines -1- t-butyl formate (3.8g, it 17.7mmol) is dissolved in methylene chloride (80mL), sequentially add triethylamine (3.5g, 35.2mmol) and 4-dimethylaminopyridine (108mg, 0.88mmol).After reaction mixture is down to 0 DEG C, chlorobenzoyl chloride (2.5g, 17.7mmol) is added drop-wise in reaction solution.After being added dropwise, reaction 3h is stirred at room temperature in reaction mixture.It is added water (40mL), separates organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give target compound (3.0g, 77% yield, colorless oil).LC-MS (ESI): m/z (M+1) 320.13.

C) 4- ((benzoyloxy) methyl) piperidines -1- carboxylic t-butyl formate (3.0g, 9.3mmol) (piperidin-4-yl) methyl benzoate: is dissolved in hydrochloric acid dioxane solution (4M, 30mL).After reaction 1h is stirred at room temperature in reaction solution, organic solvent is removed under reduced pressure.Methylene chloride (50mL) is added into crude product, at 0 DEG C, sodium hydroxide solution tune pH to 7-8 is added, separates organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give target compound (1.5g, 73% yield, colorless oil).LC-MS (ESI): m/z (M+1) 220.13.

D) (1- (4- bromophenyl) piperidin-4-yl) methyl benzoate: to (piperidin-4-yl) methyl benzoate (1.0g, it sequentially adds in tetrahydrofuran (30mL) solution 4.6mmol) to bromo-iodobenzene (2.58g, 9.1mmol), 4, bis- (diphenylphosphines) -9 of 5-, 9- xanthphos (533mg, 0.92mmol) and three (dibenzylidene) acetone, two palladium (148mg, 0.46mmol).Nitrogen is replaced 3 times, and bis- (trimethyl) silicon substrate amido lithiums (1M, 13.7mL, 13.7mmol) are added.After being stirred to react for 24 hours at room temperature, add water (10mL) quenching reaction, extracted with methylene chloride (50mL), separate organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give target compound (1.2g, crude product, yellow solid).The intermediate is directly used in without purifying to react in next step.LC-MS (ESI): m/z (M+1) 374.28.

E) (1- (4- bromophenyl) piperidin-4-yl) methanol: by (1- (4- bromophenyl) piperidin-4-yl) methyl benzoate (1.2g crude product, 3.2mmol) it is added to the in the mixed solvent of ethyl alcohol (20mL) and water (2mL), it is added sodium hydroxide (256.0mg, 6.4mmol).After reaction 2h is stirred at room temperature in reaction mixture, water (20mL) and methylene chloride (50mL) are added into reaction solution, separates organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (petroleum ether: ethyl acetate=1: 1) obtains target compound (843mg, two steps, 69% yield, yellow solid).LC-MS (ESI): m/z (M+1) 270.17.

F) (1- (4- bromophenyl) piperidin-4-yl) toluenesulfonic acid methyl esters: by (1- (4- bromophenyl) piperidin-4-yl) methanol (843mg, it 3.1mmol) is added in methylene chloride (20mL), sequentially add 4-dimethylaminopyridine (38mg, 0.3 mmol) and triethylamine (633mg, 6.3mmol).At 0 DEG C, it is slowly dropped into paratoluensulfonyl chloride (718mg, 3.8mmol).After being added dropwise, reaction 2h is stirred at room temperature in reaction mixture.Water (20mL) and methylene chloride (50mL) are added into reaction solution, separates organic phase, water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give target compound (681mg, 52% yield, yellow solid).LC-MS (ESI): m/z (M+1) 424.35.

G) N, N- dimethyl -1- (1- (4- bromophenyl) piperidin-4-yl) methylamine: by (1- (4- bromophenyl) piperidin-4-yl) toluenesulfonic acid methyl esters (681mg, it 1.6mmol) is dissolved in tetrahydrofuran (20mL), sequentially add dimethylamine hydrochloride (656mg, 8.0mmol) and potassium carbonate (1.1g, 8.0mmol).Under nitrogen protection, after reaction mixture is stirred to react for 24 hours at 50 DEG C, reaction solution is cooled to room temperature.Water (20mL) and methylene chloride (50mL) is added, separates organic phase.Water phase is extracted with methylene chloride (50mL × 2).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (methylene chloride: methanol=5: 1) obtains target compound (240mg, 52% yield, yellow solid).LC-MS (ESI): m/z (M+1) 297.35.

Intermediate N, N- dimethyl -1- (1- (4- bromophenyl) piperidin-4-yl) ethamine can using be similar to 3) synthetic method be made, starting material is 1- (tert-butoxycarbonyl) piperidines -4- acetic acid, chlorobenzoyl chloride, to bromo-iodobenzene, paratoluensulfonyl chloride and dimethylamine hydrochloride.

Embodiment 1

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) pyridine -2- base) oxygroup) -1- propylamine

A) 2- hydroxyl -7- bromopyridine simultaneously [2,3-b] pyrazine: by 2,3- diamino -5- bromopyridine (5.0g, 26.6mmol), glyoxylic acid ethyl ester (50% toluene solution, 8.0g, 39.9mmol) is mixed in dioxane (100mL).It after reaction solution is stirred to react 1h at 120 DEG C, is cooled to room temperature, ether (500mL) dilute reaction solution is added, filter, obtain target compound (4.5g, 75% yield, yellow solid).LC-MS (ESI): m/z (M+1) 226.35.

B) the chloro- 7- bromopyridine of 2- simultaneously [2,3-b] pyrazine: by 2- hydroxyl -7- bromopyridine, simultaneously [2,3-b] pyrazine (500mg, 2.2mmol) is dissolved in phosphorus oxychloride (7mL).It after reaction solution is stirred to react 3h at 90 DEG C, is cooled to room temperature, reaction solution is slowly dropped in ice water, the solid of precipitation is filtered, obtain target compound (510mg, 95% yield, yellow solid) after dry.LC-MS (ESI): m/z (M+1) 244.11.

C) 2- diazanyl -7- bromopyridine simultaneously [2,3-b] pyrazine: by the chloro- 7- bromopyridine of 2-, simultaneously [2,3-b] pyrazine (500mg, 2.05mmol) is dissolved in ethyl alcohol (5mL), is added hydrazine hydrate (1.2mL).It after reaction solution is stirred to react 1.5h at 80 DEG C, is cooled to room temperature, filters, filter cake obtains target compound (450mg, 92% yield, light yellow solid) after being drained with a small amount of ethanol washing, solid.LC-MS (ESI): m/z (M/M+2) 240.30/242.30.

D) the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine: by 2- diazanyl -7- bromopyridine simultaneously [2,3-b] pyrazine (200mg, 0.83mmol), oxinane -4- formaldehyde (95mg, 0.83mmol) is mixed in methanol (4mL).After reaction 1h is stirred at room temperature in reaction solution, solvent is removed under reduced pressure.Crude product is dissolved with methylene chloride (4mL), is added iodobenzene acetate (400mg, 1.24mmol).After reaction 10min is stirred at room temperature in reaction solution, with saturated sodium bicarbonate aqueous solution (10mL) quenching reaction, liquid separation is extracted with ethyl acetate (10mL × 3).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent), obtains target compound (200 milligrams, 72% yield, light yellow solid).LC-MS (ESI): m/z (M+1) 334.43.

E) N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2, 3-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -8- base) pyridine -2- base) oxygroup) -1- propylamine: by the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) pyrido [2, 3-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine (30mg, 0.09mmol), (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid (61mg, 0.45mmol), cesium carbonate (88mg, 0.27mmol) and [1, 1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (8mg, 0.009mmol) it is mixed in In dioxane (2.5mL) and water (0.5mL).It under nitrogen protection, after reaction solution is stirred to react 1h at 100 DEG C, is cooled to room temperature, extracts liquid separation with ethyl acetate and water.Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.It is isolated and purified with preparative liquid chromatography (C18 column, 0-100% acetonitrile/water are mobile phase), obtains target compound (15mg, 38% yield, white solid).LC-MS (ESI): m/z (M+1) 434.50. ¹H NMR (400MHz, DMSO-d ₆): δ 9.55 (s, 1H), 9.25 (d, J=1.9Hz, 1H), 8.75 (d, J=2.5Hz, 1H), 8.69 (d, J=2.0Hz, 1H), 8.29 (dd, J=8.7,2.6Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 4.45-4.37 (m, 2H), 4.33-4.25 (m, 1H), 4.06-3.94 (m, 2H), 3.77-3.68 (m, 2H), 2.46-2.41 (m, 2H), 2.21 (s, 6H), 2.18-1.82 (m, 6H).

Embodiment 2

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine

It is made using the synthetic method similar to described embodiment 1e, starting material is the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine (embodiment 1d) and N, N- dimethyl -3- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) phenoxy group) -1- propylamine.LC-MS (ESI): m/z (M+1) 433.39. ¹H NMR (400MHz, DMSO-d ₆): δ 9.53 (s, 1H), 9.22 (d, J=2.0Hz, 1H), 8.63 (d, J=2.0Hz, 1H), (7.88 d, J=8.8Hz, 2H), 7.18 (d, J=8.8Hz, 2H), 4.27-4.21 (m, 1H), 4.11 (t, J=6.4Hz, 2H), 4.06-4.00 (m, 2H), 3.71 (t, J=10.2Hz, 2H), 2.39 (t, J=7.1Hz, 2H), 2.23-2.09 (m, 8H), 2.07-1.99 (m, 2H), 1.93-1.86 (m, 2H).

Embodiment 3

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine

A) 2- hydroxyl -7- bromine quinoxaline: 2- hydroxy quinoxaline (5g, 34.2mmol) is dissolved in acetic acid (50mL), and bromine (8.2g, 51.2mmol) is slowly added dropwise.It after reaction 6h is stirred at room temperature in reaction solution, filters, filter cake is washed with a small amount of ether, and solid obtains target compound (6.1g, 79% yield, yellow solid) after draining.LC-MS (ESI): m/z (M+1) 225.11.

B) the chloro- 7- bromine quinoxaline of 2-: 2- hydroxyl -7- bromine quinoxaline (3g, 13.3mmol) is dissolved in phosphorus oxychloride (25mL), and DMF (3 drop) is added and is used as catalyst.It after reaction solution is stirred to react 3h at 120 DEG C, is cooled to room temperature, is concentrated under reduced pressure, crude product is diluted with ethyl acetate (50mL), is slowly dropped in saturated sodium bicarbonate aqueous solution (200mL).Liquid separation extraction, organic phase are washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, petroleum ether: ethyl acetate=2: 1 is eluant, eluent), obtains target compound (1.3g, 40% yield, yellow solid).LC-MS (ESI): m/z (M+1) 243.20.

C) 2- diazanyl -7- bromine quinoxaline: the chloro- 7- bromine quinoxaline (1.3g, 5.3mmol) of 2- is dissolved in ethyl alcohol (15mL), is added hydrazine hydrate (2.0mL).It after reaction solution is stirred to react 1h at 80 DEG C, is cooled to room temperature, filters, filter cake obtains target compound (1.2g, 95% yield, white solid) after being drained with a small amount of ethanol washing, solid.LC-MS (ESI): m/z (M+1) 239.10.

D) the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline: by 2- diazanyl -7- bromine quinoxaline (200mg, 0.83mmol), oxinane -4- formaldehyde (95mg, 0.83mmol) is mixed in methanol (4mL).After reaction 1h is stirred at room temperature in reaction solution, solvent is removed under reduced pressure.Crude product is dissolved with methylene chloride (10mL), is added iodobenzene acetate (400mg, 1.24mmol).After reaction 10min is stirred at room temperature in reaction solution, with saturated sodium bicarbonate aqueous solution (10mL) quenching reaction, liquid separation is extracted with ethyl acetate (10mL, three times).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=20: 1 is eluant, eluent), obtains target compound (250mg, 90% yield, yellow solid).LC-MS (ESI): m/z (M+1) 333.20.

E) N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine: by the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline (25mg, 0.075mmol), (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid (50mg, 0.22mmol), cesium carbonate (75mg, 0.23mmol) and [1, 1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (7mg, 0.0075mmol) be mixed in dioxane (2.5mL) and water ( In 0.5mL).It under nitrogen protection, after reaction solution is stirred to react 1h at 100 DEG C, is cooled to room temperature, extracts liquid separation with ethyl acetate (5mL) and water (5mL).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.It is isolated and purified with preparative liquid chromatography (C18 column, 0-100% acetonitrile/water are mobile phase), obtains target compound (13mg, 40% yield, white solid).LC-MS (ESI): m/z (M+1) 433.55. ¹H NMR (400MHz, DMSO-d ₆): δ 9.33 (s, 1H), 8.66 (d, J=2.5Hz, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 8.04 (d, J=8.5Hz, 1H), 7.02 (d, J=8.6Hz, 1H), 4.38 (t, J=6.6Hz, 2H), 4.29-4.20 (m, 1H), 4.06-3.99 (m, 2H), 3.75-3.67 (m, 2H), 2.42-2.35 (m, 2H), 2.26-2.14 (m, 8H), 2.09-1.99 (m, 2H), 1.95-1.85 (m, 2H).

Embodiment 4

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine

It is made using the synthetic method similar to described embodiment 3e, starting material is N, N- dimethyl -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron, penta ring -2- base) phenoxy group) -1- propylamine and the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 3d).LC-MS (ESI): m/z (M+1) 432.65. ¹H NMR (400MHz, DMSO-d ₆): δ 9.30 (s, 1H), 8.30 (d, J=1.6Hz, 1H), 8.16 (d, J=8.4Hz, 1H), 8.01 (dd, J=8.5,1.7Hz, 1H), 7.79 (d, J=8.8Hz, 2H), 7.14 (d, J=8.8Hz, 2H), 4.21-4.15 (m, 1H), 4.13-4.03 (m, 4H), 3.73-3.65 (m, 2H), 2.49-2.46 (m, 2H), 2.24 (s, 6H), 2.22-2.16 (m, 2H), 2.10-1.99 (m, 2H), 1.96-1.89 (m, 2H).

Embodiment 5

N, N- dimethyl -3- ((6- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridin-3-yl) oxygroup) -1- propylamine

A) 1- (tetrahydro -2H- pyrans -4- base) -8- (4, 4, 5, 5- tetramethyl -1, 3, penta ring -2- base of 2- dioxy boron)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline: by the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline (310mg, 0.93mmol), connection boric acid pinacol ester (353mg, 1.39mmol), potassium acetate (275mg, 2.81mmol) and [1, 1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (76mg, it 0.093mmol) is added in dioxane (15 mL).Under nitrogen protection, reaction mixture is cooled to room temperature after being stirred to react 16h at 90 DEG C, is filtered, and filtrate decompression is concentrated to get crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (300mg, 85% yield, yellow solid).LC-MS (ESI): m/z (M+1) 381.30.B) N, N- dimethyl -3- ((6- (1- (tetrahydro -2H- pyrans -4- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) pyridin-3-yl) oxygroup) -1- propylamine: by N, N- dimethyl -3- ((6- bromopyridine -3- base) oxygroup) -1- propylamine (50mg, 0.19mmol), 1- (tetrahydro -2H- pyrans -4- base) -8- (4, 4, 5, 5- tetramethyl -1, 3, 2- dioxy boron pentane -2- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline (73mg, 0.19mmol), cesium carbonate (125mg, 0.38mmol) and [1, 1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (15mg , 0.02mmol) and it is added to the in the mixed solvent of dioxane (2.5mL) and water (0.5mL).Under nitrogen protection, reaction mixture is cooled to room temperature after being stirred to react 2h at 90 DEG C, is filtered, is concentrated under reduced pressure to give crude product.It isolates and purifies to obtain target compound (8mg, 23% yield, white solid) with preparative liquid chromatography (C18 column, 0-100% acetonitrile/water are mobile phase).LC-MS (ESI): m/z (M+1) 433.35. ¹H NMR (400MHz, CDCl ₃): 9.25 (s of δ, 1H), 9.07 (d, J=1.2Hz, 1H), 8.46 (d, J=2.7Hz, 1H), 8.19 (d, J=8.5Hz, 1H), 8.12 (dd, J=8.4Hz, 1.5Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.36 (dd, J=8.8Hz, 2.9Hz, 1H), 4.29-4.21 (m, 2H), 4.18 (t, J=6.3Hz, 2H), 3.99-3.92 (m, 1H), 3.86-3.78 (m, 2H), 2.58 (t, J=7.1Hz, 2H), 2.43-2.23 (m, 10H), 2.10-2.05 (m , 2H).

Embodiment 6-10 and 12-19 apply the synthetic method similar to described embodiment 5 to be made, starting material is 1- (tetrahydro -2H- pyrans -4- base) -8- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline and the aryl or heteroaryl that replace accordingly.Embodiment 11 is that the compound of embodiment 10 and paraformaldehyde heat reaction in formic acid and be made.

Embodiment 20-22 applies the synthetic method similar to described embodiment 3 to be made, starting material is N, N- dimethyl -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron, penta ring -2- base) phenoxy group) -1- propylamine and the bromo- 1- of corresponding 8- replace-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.

Following compounds can also be synthesized by known method by those skilled in the art and are made.

Embodiment 23

N, N- dimethyl -3- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine

A) (2R; 6S) -4- (chloroformyl) -2,6-dimethyl-piperizine -1- t-butyl carbonate: triphosgene (1.3g, 4.4mmol) is dissolved in anhydrous methylene chloride (20mL); it is added pyridine (1.03g, 13.0mmol).After reaction mixture is cooled to 0 DEG C, methylene chloride (5mL) solution of (2R, 6S) -2,6-dimethyl-piperizine -1- t-butyl carbonate (1.4g, 6.5mmol) is slowly added drop-wise in reaction system.After being added dropwise, reacting liquid temperature is warmed to room temperature and reaction 6h is stirred at room temperature.Dilute hydrochloric acid (1M is added into reaction solution, 50mL), mixture is extracted with methylene chloride (30mL × 2), combined organic phase is dry with anhydrous sodium sulfate, removing organic solvent is concentrated under reduced pressure and obtains product (1.41g, 100% yield, yellow liquid), which is directly used in subsequent reactions without further purification.

B) (2R; 6S) -4- (2- (7- bromine quinoxaline -2- base) hydrazine -1- formoxyl) -2; 6- lupetazin -1- t-butyl carbonate: at room temperature; by the bromo- 2- diazanyl quinoxaline (700mg of 7-; it 2.93mmol) is dissolved in anhydrous methylene chloride (10mL); it is added n,N-diisopropylethylamine (1.6mL, 8.8mmol).(2R, 6S) -4- (chloroformyl) -2,6-dimethyl-piperizine -1- t-butyl carbonate (1.23g, 4.4mmol) is added in reaction system.After reaction is stirred at room temperature 3 days in reaction mixture, it is added in saturated sodium bicarbonate aqueous solution (20mL).After liquid separation, water phase is extracted with methylene chloride (50mL).Merge organic phase, is washed with saturated common salt, anhydrous sodium sulfate dries, filters, and organic solvent is removed under reduced pressure and obtains crude product.Column chromatographic isolation and purification (silica gel, petroleum ether: ethyl acetate=5: 1 is eluant, eluent) obtains target compound (480mg, 35% yield, white solid).LC-MS (ESI): m/z (M+1) 479.17.

C) bromo- the 1- ((2R of 8-, 6S) -3, 5- lupetazin -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline: at room temperature, by (2R, 6S) -4- (2- (7- bromine quinoxaline -2- base) hydrazine -1- formoxyl) -2, 6- lupetazin -1- t-butyl carbonate (480mg, it 1.0mmol) is dissolved in phosphorus oxychloride (5mL), after reaction mixture is stirred to react 1h at 100 DEG C, it is concentrated under reduced pressure and removes phosphorus oxychloride, saturated solution of sodium bicarbonate (10mL) is added to be quenched, and it is extracted with ethyl acetate (20mL).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and organic solvent is removed under reduced pressure and obtains crude product.Column chromatographic isolation and purification (silica gel, petroleum ether: ethyl acetate=5: 1 is eluant, eluent) obtains target compound (228mg, 63% yield, white solid).LC-MS (ESI): m/z (M+1) 361.11.

D) bromo- the 1- ((2R of 8-, 6S) -3, 4, 5- tri methyl piperazine -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline: at room temperature, by bromo- the 1- ((2R of 8-, 6S) -3, 5- lupetazin -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline (228g, it 0.63mmol) is dissolved in methanol (2mL), then successively the formalin of formic acid and 40% is added, after reaction mixture is stirred to react 40h at 70 DEG C, it is concentrated under reduced pressure and removes solvent, saturated solution of sodium bicarbonate (10mL) is added to be quenched, and it is extracted with ethyl acetate (20mL).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and organic solvent is removed under reduced pressure and obtains crude product.Column chromatographic isolation and purification (silica gel, petroleum ether: ethyl acetate=5: 1 is eluant, eluent) obtains target compound (162mg, 68% yield, white solid).LC-MS (ESI): m/z (M+1) 375.14.

E) N, N- dimethyl -3- (4- (1- ((2R, 6S) -3, 4, 5- tri methyl piperazine -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) phenoxy group) propyl- 1- amine: at room temperature, by bromo- the 1- ((2R of 8-, 6S) -3, 4, 5- tri methyl piperazine -1- base)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline (100mg, 0.27mmol), 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester (165mg, 0.54mmol), [1, 1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (22mg, 0.027mmol) and cesium carbonate (176mg, 0.54mmol) it is added To the in the mixed solvent of dioxane (2mL) and water (0.5mL), replace nitrogen 3 times.Reaction mixture after microwave reaction 1h, is cooled to room temperature at 100 DEG C.Filtering, is removed under reduced pressure organic solvent and obtains crude product.It isolates and purifies to obtain target compound (20mg, 15% yield, yellow solid) with preparative liquid chromatography (C18 column, 0-100% acetonitrile/water are mobile phase).LC-MS (ESI): m/z (M+1) 474.12. ¹H NMR (400MHz, DMSO-d ₆): δ 9.16 (s, 1H), 8.70 (m, 1H), 8.06 (d, J=8.4Hz, 1H), 7.92 (d, J=8.4Hz, 1H), 7.70 (d, J=8.4Hz, 2H), 7.12 (d, J=8.7Hz, 2H), 4.10 (t, J=6.3Hz, 2H), 3.54-3.29 (m, 4H), 2.93-2.78 (m, 2H), 2.57-2.52 (m, 2H), 2.30-2.23 (m, 9H), 1.96-1.89 (m, 2H), 1.10 (s, 6H).

Embodiment 24-25 and 27-28 apply the synthetic method similar to described embodiment 3 to be made, starting material is that (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid and the bromo- 1- of corresponding 8- replace-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.

The synthetic method that the application of embodiment 26 is similar to described embodiment 23 is made, starting material is (6- (3- (dimethylamino) propyl) pyridin-3-yl) boric acid and bromo- the 1- ((2R of 8-, 6S) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline.

N is made in the synthetic method that the application first of embodiment 29 is similar to described embodiment 3, N- dimethyl -3- (4- (1- (1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1H- imidazol-4 yl)-(1, 2, 4) triazole simultaneously [4, 3-a] quinoxaline -8- base) phenoxy group) -1- propylamine, then room temperature reaction deprotection in methylene chloride under intermediate acid condition existing for hydrochloric acid/dioxane, target compound N is made, N- dimethyl -3- (4- (1- (1H- imidazol-4 yl)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) phenoxy group) -1- propylamine.

Following compounds can also be synthesized by known method by those skilled in the art and are made.

Embodiment 30

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine

It is made using the synthetic method for being similar to described embodiment 1, starting material 3,4- diamino -6- chloropyridine, glyoxylic acid ethyl ester, hydrazine hydrate, oxinane -4- formaldehyde and 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester.LC-MS (ESI): m/z (M+H) ⁺433.07。 ¹H NMR (400MHz, DMSO-d ₆): δ 9.36 (s, 1H), 9.34 (s, 1H), 8.33 (s, 1H), 8.16 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.32-4.23 (m, 1H), 4.18-4.08 (m, 2H), 4.08-3.97 (m, 2H), (3.77 t, J=10.6Hz, 2H), (2.38 t, J=6.8Hz, 2H), 2.23-2.13 (m, 7H), 2.11-1.95 (m, 3H), 1.94-1.84 (m, 2H).

Embodiment 31

N, N- dimethyl -3- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine

A) 3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine: at room temperature, by 6- chloropyridine simultaneously [2,3-b] pyrazine -3 (4H) -one (480mg, 2.65mmol) it is dissolved in N, in dinethylformamide (10mL), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 1.51g is sequentially added, 2.91mmol) and N, N- diisopropylethylamine (DIPEA, 0.67mL, 3.98mmol).After reaction 30min is stirred at room temperature in reaction mixture, it is cooled to 0 DEG C, is added hydrazine hydrate (0.17mL, 2.91mmol).Reaction mixture continuation is stirred to react 30min at 0 DEG C.Saturated sodium bicarbonate aqueous solution (10mL) is added, solid is precipitated afterwards, filter, filter cake is washed with water (5mL), obtains target compound (480mg, 92% yield, yellow solid) after dry.LC-MS (ESI): m/z (M+1) 196.18.

B) the chloro- 9- of 2- (tetrahydro -2H- pyrans -4- base) pyridine [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine: by 3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine (146mg, 0.75mmol), oxinane -4- formaldehyde (103mg, 0.9mmol) is mixed in methanol (4mL).After reaction 1h is stirred at room temperature in reaction solution, solvent is removed under reduced pressure, obtains the chloro- 3- of crude product 6- (2- ((tetrahydro -2H- pyrans -4- base) methylene) diazanyl) pyrido [2,3-b] pyrazine.The intermediate crude product is dissolved with methylene chloride (4mL), is added iodobenzene acetate (483mg, 1.5mmol).After reaction 10min is stirred at room temperature in reaction solution, with saturated sodium bicarbonate aqueous solution (10mL) quenching reaction, liquid separation is extracted with methylene chloride (10mL × 3).Organic phase is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatographic isolation and purification (silica gel, methylene chloride: methanol=10: 1 is eluant, eluent) obtains target compound (104mg, 48% yield, light yellow solid).LC-MS (ESI): m/z (M+1) 290.17.

C) N, N- dimethyl -3- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3, 2-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -2- base) phenoxy group) -1- propylamine: by the chloro- 9- of 2- (tetrahydro -2H- pyrans -4- base) pyridine [3, 2-e] [1, 2, 4] triazol [4, 3-a] pyrazine (28mg, 0.11mmol), 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester (46mg, 0.15mmol), cesium carbonate (65mg, 0.20mmol) and tetrakis triphenylphosphine palladium (12mg, 0.01mmol) it is added to the in the mixed solvent of dioxane (1.0mL) and water (0.2mL).Under nitrogen protection, reaction mixture is cooled to room temperature after being stirred to react 1h at 100 DEG C, is filtered, is concentrated under reduced pressure to give crude product.It isolates and purifies to obtain target compound (5mg, 12% yield, white solid) with preparative liquid chromatography (C18 column, 0-100% acetonitrile/water are mobile phase).LC-MS (ESI): m/z (M+1) 433.60. ¹H NMR (400MHz, DMSO-d ₆): δ 9.33 (s, 1H), 8.54 (d, J=8.5Hz, 1H), 8.32 (d, J=8.5Hz, 1H), 8.22 (d, J=8.8Hz, 2H), 7.19 (d, J=8.8Hz, 2H), 4.53-4.47 (m, 1H), 4.16-4.05 (m, 4H), 3.68 (t, J=10.8Hz, 2H), 2.46-2.42 (m, 2H), 2.29-2.13 (m, 8H), 2.09-2.01 (m, 2H), 1.95-1.88 (m, 2H).

Embodiment 32

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine

A) 7- bromine quinoxaline -2- amine: the bromo- 2- chloro-quinoxaline (1.0g, 4.13mmol) of 7- and ammonium hydroxide (7mL) are added in Isosorbide-5-Nitrae-dioxane (7mL).After reaction mixture is stirred to react 5h at 70 DEG C, it is cooled to room temperature.It is added water (10mL), is extracted with ethyl acetate (30mL × 2).Merge organic phase, is washed with saturated salt solution (50mL), anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatography (silica gel, petroleum ether: ethyl acetate=3: 1 is eluant, eluent) isolates and purifies to obtain target compound (500mg, 54.2% yield, yellow solid).LC-MS (ESI): m/z (M+1) 223.99.

B) the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline: by 7- bromine quinoxaline -2- amine (500mg, 2.24mmol) it is added in N-Methyl pyrrolidone (1mL) with the bromo- 1- of 2- (tetrahydro -2H- pyrans -4- base) ethyl ketone (462mg, 2.24mmol).Reaction mixture nitrogen protection is cooled to room temperature after being stirred to react 1h at 150 DEG C.It is added water (10mL), is extracted with ethyl acetate (20mL × 2).Merge organic phase, is washed with saturated salt solution (20mL × 2), anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give crude product.Column chromatography (silica gel, methylene chloride: methanol=30: 1 is eluant, eluent) isolates and purifies to obtain target compound (120mg, 16.2% yield, yellow solid).LC-MS (ESI): m/z (M+1) 332.14.

C) N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine: application is mentioned similar to the synthetic method system of described embodiment 1e, starting material is the bromo- 1- of 8- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline and 3- (N, N- dimethylamino) propoxyl group phenyl boric acid pinacol ester.LC-MS (ESI): m/z (M+1) 431.07. ¹H NMR (400MHz, CDCl ₃) δ 9.26 (s, 1H), 8.24-8.17 (m, 2H), 7.92 (dd, J=8.8,2.1Hz, 1H), 7.71 (d, J=8.7Hz, 2H), 7.03 (d, J=8.7Hz, 2H), 6.53 (s, 1H), 4.15-4.08 (m, 4H), 3.54 (td, J=12.0,2.1Hz, 2H), 3.20-3.13 (m, 1H), (2.63 t, J=6.0Hz, 2H), 2.38 (s, 6H), 2.12-2.05 (m, 4H), 2.00-1.93 (m, 2H).

Following compound 33-38 is prepared using with the similar method of embodiment 32 and corresponding raw material.

Embodiment 33

N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine (M.W.431.54)

Embodiment 34

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine (M.W.430.55)

Embodiment 35

N, N- dimethyl -3- ((5- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine (M.W.432.53)

Embodiment 36

N, N- dimethyl -3- (4- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine (M.W.431.54)

Embodiment 37

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-a] quinoxaline -8- base) phenoxy group) -1- propylamine (M.W.430.55)

Embodiment 38

N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) H- pyrrolo- [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine (M.W.429.56)

The application of embodiment 39 is made similar to the synthetic method of described embodiment 1e, and starting material is 1- (tetrahydro -2H- pyrans -4- base) bromo- [1,2,4] triazole of -8- simultaneously [4,3-a] quinoxaline and phenyl boric acid.

Embodiment 40 is that the compound of embodiment 10 and sodium hydrogen, iodomethane are reacted at room temperature in n,N-Dimethylformamide and be made.

The intermediate respectively protected by tertbutyloxycarbonyl is made similar to the synthetic method of described embodiment 5b in embodiment 41-43 first application, is then deprotected and is made (such as in hydrochloric acid dioxane solution) in acid condition.

Embodiment 44-54 applies the synthetic method similar to described embodiment 5b to be made, starting material is 1- (tetrahydro -2H- pyrans -4- base) -8- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline and corresponding N, N- dimethyl -1- (the bromo- substituted-phenyl of 4-) piperidines -4- amine or N, N- dimethyl -1- (6- bromopyridine -3- base) piperidines -4- amine or N, N- dimethyl -1- (1- (4- bromophenyl) piperidin-4-yl) alkylamine.

Embodiment 55-63 applies the synthetic method similar to described embodiment 23 to be made, starting material is the bromo- 1- of 8- ((2R, 6S) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline and corresponding N, N- dimethyl -3- (4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base) -2- substituent phenoxy) -1- propylamine or N, N- dimethyl -1- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron)-substituted-phenyl) piperidines -4- amine.

The synthetic method that the application of embodiment 64 is similar to described embodiment 3 is made, starting material is 2- diazanyl -7- bromine quinoxaline, 4- (dimethylamino) piperidines -1- phosgene and N, N- dimethyl -1- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) phenyl) piperidines -4- amine.

The synthetic method that the application of embodiment 65 is similar to described embodiment 31 is made, starting material is 2- hydroxyl -7- bromine quinoxaline, hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, hydrazine hydrate, 2- morpholine acetaldehyde and N, N- dimethyl -1- (4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron, penta ring -2- base) phenyl) piperidines -4- amine.

Intermediate methyl (1- (4- (1- (morpholine methyl)-[1 is made similar to the synthetic method of described embodiment 3e in the application first of embodiment 66, 2, 4] triazol [4, 3-a] quinoxaline -8- base) phenyl) piperidin-4-yl) (starting material is intermediate the 4- ((8- bromo- [1 of embodiment 65 to t-butyl carbamate, 2, 4] triazol [4, 3-a] quinoxaline -1- base) methyl) morpholine and 4- (4- (N- tertbutyloxycarbonyl methylamino) piperidyl) phenylboric acid pinacol ester), then the intermediate is deprotected in acid condition obtains target compound N- methyl-1-(4- (1- (morpholinyl methyl)-[1, 2, 4] triazole simultaneously [4, 3-a] quinoxaline -8- base) phenyl) piperidines -4- amine.

Following compounds can also be synthesized by known method by those skilled in the art and are made.

The synthetic method that the application of embodiment 67-69 and 71 is similar to described embodiment 31 is made, starting material is 7- chloropyridine simultaneously [3,4-b] pyrazine -2 (1H) -one, hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, hydrazine hydrate, oxinane -4- formaldehyde and corresponding phenylboric acid pinacol ester.

Intermediate methyl (1- (4- (1- (tetrahydropyran -4-base) pyrido [3 is made similar to the synthetic method of described embodiment 3e in the application first of embodiment 70, 4-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -8- base) phenyl) piperidin-4-yl) (starting material is intermediate 8- chloro- 1- (tetrahydropyran -4-base) pyrido [3 of embodiment 67-69 to t-butyl carbamate, 4-e] [1, 2, 4] triazole simultaneously [4, 3-a] pyrazine and 4- (4- (N- tertbutyloxycarbonyl methylamino) piperidyl) phenylboric acid pinacol ester), then the intermediate is deprotected in acid condition obtains target compound N- methyl-1-(4- (1- (tetrahydropyran -4-base) pyrido [3, 4-e] [ 1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenyl) piperidines -4- amine.

Embodiment 72,76,78-79 and 90-93 apply the synthetic method similar to described embodiment 31 to be made, starting material is 6- chloropyridine simultaneously [2,3-b] pyrazine -3 (4H) -one, hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, hydrazine hydrate, oxinane -4- formaldehyde or 2- morpholine acetaldehyde or 4- (dimethylamino) piperidines -1- phosgene and corresponding boric acid pinacol ester.

The intermediate respectively protected by tertbutyloxycarbonyl is made similar to the synthetic method of described embodiment 31c in the application first of embodiment 73-75 and 77, is then deprotected and is made (such as in hydrochloric acid dioxane solution) under acidic conditions.

Embodiment 80-89 applies the synthetic method similar to described embodiment 23b-e to be made; starting material is the chloro- 3- hydrazino pyridine of 6- simultaneously [2; 3-b] pyrazine; (2R; 6S) -4- (chloroformyl) -2; 6- lupetazin -1- t-butyl carbonate, formalin and corresponding phenylboric acid pinacol ester.

The intermediate protected by tertbutyloxycarbonyl is made similar to the synthetic method of described embodiment 23e in embodiment 94-97 first application; then it is deprotected and is made (such as in hydrochloric acid dioxane solution) under acidic conditions; starting material is bromo- the 1- ((2R of 8-; 6S) -3; 4,5- tri methyl piperazine -1- bases)-[1,2; 4] triazole simultaneously [4,3-a] quinoxaline (embodiment 23d) and corresponding replaces phenyl boric acid pinacol ester.

The application of embodiment 98 is made similar to the synthetic method of described embodiment 23d-e, and starting material is the bromo- 1- of 8- ((2R, 6S) -3,5- lupetazin -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 23c), iodoethane and N, N- dimethyl -1- (4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron, penta ring -2- base) -2- (trifluoromethyl)-phenyl) piperidines -4- amine.

Embodiment 99-116 applies the synthetic method similar to described embodiment 3d-e to be made, and starting material is 2- diazanyl -7- bromine quinoxaline, and corresponding heterocycle phosgene replaces phenyl boric acid pinacol ester with corresponding.

Embodiment 117-120 applies the synthetic method similar to described embodiment 23e to be made, starting material is chloro- the 9- ((3S of 2-, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine (intermediate of embodiment 80) and corresponding phenylboric acid pinacol ester.

The application of embodiment 121 is made similar to the synthetic method of described embodiment 23d-e, starting material is chloro- the 9- ((3S of 2-, 5R) -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine (intermediate of embodiment 80), iodoethane and N, N- dimethyl -1- (4- (4,4,5,5- tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) -2- (trifluoromethyl) phenyl) piperidines -4- amine.

The application of embodiment 122 is similar to the synthetic method preparation of described embodiment 31c-d, starting material is 3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine, (3S, 5R) -4- isopropyl -3,5- lupetazin -1- phosgene and N, N- dimethyl -1- (4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron, penta ring -2- base) -2- (trifluoromethyl) phenyl) piperidines -4- amine.

Embodiment 123-145 applies the synthetic method similar to described embodiment 31b-e to be made, starting material is 3- diazanyl -6- chloropyridine simultaneously [2,3-b] pyrazine (embodiment 31a), oxinane -4- formaldehyde or corresponding substituted heterocycle phosgene and corresponding phenylboric acid pinacol ester.

Embodiment 146-151 applies the synthetic method similar to described embodiment 23e to be made, starting material is bromo- the 1- ((2R of 8-, 6S) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline (embodiment 23d) and corresponding phenylboric acid pinacol ester.

Embodiment 152

N is measured using external ATM kinase assays, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine and its homologue be to the In-vitro Inhibitory Effect of ATM

ATM (source of people) is added in the reaction solution of GST-cMyc-p53 containing 30nM and 10 μM of Mg/ATP to be incubated for, untested compound (or the reference compound AZD0156) liquid storage of 50 times of concentration being dissolved in 100%DMSO is then added to 10/1/0.1/0.01/0.001 μM of final concentration, mixes.The starting reaction of Mg/ATP mixture is added, after being incubated at room temperature 30 minutes, the stop bath quenching reaction containing EDTA is added.Finally, the detection buffer for the anti-phosphoric acid Ser15 antibody that addition is marked containing the d2 anti-GST monoclonal antibody marked and for the europium of phosphorylation p53.Then the read plate under time-resolved fluorescence mode, according to equation: HTRF=10000 × (Em _665nm/Em _620nm) measurement time-homogeneous resolved fluorometric (HTRF) signal.Each compound sample in duplicate repeats.Testing negative control is all constituents for lacking ATM, and the positive terminates reaction for EDTA is added.Table 1 summarizes the ATM kinase inhibition data (inhibiting rate %) of compound.

1. N of table, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine and its homologue be to the inhibiting effect of ATM kinases

Untested compound is subjected to continuous series in 1: 3 and 1: 10 ratio with 100%DMSO respectively and is diluted to 10 concentration (the last one concentration is DMSO negative control), is added in ATM culture medium, until final concentration is respectively 10,3,1,0.3,0.1,0.03,0.01,0.003,0.001 and 0uM, using above-mentioned described method is similar to, the detection of ATM kinase inhibition is carried out.Calculate IC ₅₀The curvilinear equation of value are as follows:

Wherein C is compound concentration, and D is slope factor.Table 2 summarizes the ATM kinase inhibition IC of compound ₅₀Value.

2. N of table, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine and its homologue be to the In-vitro Inhibitory Effect (IC of ATM ₅₀Value)

Embodiment	3	4
IC 50(nM)	19	9

Therefore, it is measured through ATM kinases (source of people) detection method, N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 4) and its homologue be to the depression effect having had of ATM kinases.For example, embodiment 57 is greater than 50% to the inhibition of ATM kinases in 1nM

Embodiment 153

N is measured using MTT detection method, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine combines the inhibiting effect that CPT-11 increases human colon cancer cell SW620 with its homologue

By the SW620 cell culture passages newly recovered to growth conditions are good, degrees of fusion 90% or so, start for testing.SW620 cell is digested with pancreatin, 800rpm is centrifuged 5min, abandons supernatant, is resuspended, and count with fresh training base (1640 culture medium+10%FBS of RPMI), is seeded to 96 porocyte culture plates with suitable cell hole density, is placed in 37 DEG C of 5%CO ₂Incubator overnight incubation.Untested compound and reference compound AZD0156 mother liquor carry out continuous series in 1: 3 and 1: 10 ratio with DMSO respectively and be diluted to 8 concentration: first concentration is 10 μM or 1 μM, the last one concentration is that (0 μM, DMSO final concentration of 1 is ‰) for DMSO negative control.Each concentration takes 5 μ L to be added to 120 μ L training base (25 times of dilutions), and oscillation mixes.The cell of overnight incubation is taken, culture medium is removed, the fresh culture of 195 μ L CPT-11 containing 205nM is added in every hole, then is separately added into the Pei Ji for the tested material containing respective concentration that 5 μ L have diluted, and culture plate is then placed in 37 DEG C of 5%CO ₂Incubator culture 5d.Stoste is removed to continue to cultivate after every hole adds fresh serum free DMEM training base of the 100 μ L containing MTT (0.5mg/mL).Stoste is removed after 4h, 100 μ L DMSO are added in every hole, are protected from light concussion 10min, are placed in the light absorption value that multi-functional readout instrument reads 552/630/690nm wavelength.Data are analyzed with software Graph Pad Prism 6.0, the inhibitory activity of compound on intracellular proliferation is using cell survival rate and compound concentration as coordinate plot.IC ₅₀Value is with S-shaped dose-effect curve equation model, curvilinear equation are as follows: Y=100/ (1+10^ (LogC-LogIC ₅₀)), wherein C is compound concentration.

Table 3 summarizes the inhibiting effect data (IC that compound joint CPT-11 increases human colon cancer cell SW620 ₅₀)。

3. N of table, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine combines the inhibiting effect that CPT-11 increases human colon cancer cell SW620 with its homologue

Embodiment	1	2	3	4	5	6
IC 50(nm)	> 10 5	> 10 5	661.4	328.3	> 10 5	> 10 5
Embodiment	7	8	9	10	11	12
IC 50(nm)	3104	3299	1939	5212	> 10 5	173.4

Embodiment	13	14	15	18	20	21
IC 50(nm)	> 10 5	> 10 5	485.4	> 10 5	143.5	334.3
Embodiment	22	23	26	27	29	30
IC 50(nm)	412.8	65.14	56.97	469.6	1211	> 10 4
Embodiment	31	37	39	40	41	42
IC 50(nm)	262.2	4249	> 10 5	> 10 5	455.5	211.2
Embodiment	43	44	45	46	47	48
IC 50(nm)	357.2	152.0	170.3	611.8	127.7	184.4
Embodiment	49	50	51	52	53	54
IC 50(nm)	1032	> 10 4	> 10 4	> 10 4	> 10 5	> 10 5
Embodiment	57	58	59	64	65	66
IC 50(nm)	11.80	47.47	14.40	> 10 4	402.1	589.3
Embodiment	67	68	69	70	71	72
IC 50(nm)	> 10 5	> 10 5	> 10 4	> 10 4	> 10 5	62.85
Embodiment	73	74	75	76	77	78
IC 50(nm)	190.9	199.1	157.9	817.8	1014	664.2
Embodiment	79	80	81	82	83	84
IC 50(nm)	1983	163.5	138.0	189.3	147.9	70.47
Embodiment	85	90	94	96	102	103
IC 50(nm)	41.29	981.0	13.02	15.03	21.12	176.2
Embodiment	104	111	112	117	119	139
IC 50(nm)	28.24	16.18	21.89	47.48	43.07	262.1
Embodiment	140	AZD0156
IC 50(nm)	213.4	10.04

Therefore, it is measured through MTT detection method, N, N- dimethyl -3- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 23) and its homologue have inhibiting effect to the growth of SW620 cell.Plurality of embodiment, such as embodiment 57, the inhibiting effect increased to SW620 cell are suitable with AZD0156.

Embodiment 154

N is measured using MTT detection method, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine and its homologue inhibiting effect that human breast cancer cell MDA-MB-468 is increased

By the MDA-MB-468 cell culture passages newly recovered to growth conditions are good, degrees of fusion 90% or so, start for testing.MDA-MB-468 cell is digested with pancreatin, 800rpm is centrifuged 5min, abandons supernatant, is resuspended, and count with fresh training base (1640 culture medium+10%FBS of RPMI), is seeded to 96 porocyte culture plates with suitable cell hole density, is placed in 37 DEG C of 5%CO ₂Incubator overnight incubation.Untested compound or reference compound AZD0156 mother liquor carry out continuous series in 1: 3 and 1: 10 ratio with DMSO respectively and be diluted to 8 concentration: first concentration is 10 μM or 1 μM, the last one concentration is that (0 μM, DMSO final concentration of 1 is ‰) for DMSO negative control.Each concentration takes 5 μ L to be added to 120 μ L training base (25 times of dilutions), and oscillation mixes.The cell of overnight incubation is taken, culture medium is removed, 195 μ L fresh cultures (RPMI 1640+5%FBS) are added in every hole, then are separately added into the Pei Ji for the tested material containing respective concentration that 5 μ L have diluted, and culture plate is then placed in 37 DEG C of 5%CO ₂Incubator culture 7d (wherein dressing in the 4th day once continues to cultivate).Stoste is removed to continue to cultivate after every hole adds fresh serum free DMEM training base of the 100 μ L containing MTT (0.5mg/mL).Stoste is removed after 4h, 100 μ L DMSO are added in every hole, are protected from light concussion 10min, are placed in the light absorption value that multi-functional readout instrument reads 552/630/690nm wavelength.Data are analyzed with software Graph Pad Prism 6.0, the inhibitory activity of compound on intracellular proliferation is using cell survival rate and compound concentration as coordinate plot.IC ₅₀Value is with S-shaped dose-effect curve equation model, curvilinear equation are as follows: Y=100/ (1+10^ (LogC-LogIC ₅₀)), wherein C is compound concentration.

Table 4 summarizes the inhibiting effect data (IC that compound increases human colon cancer cell MDA-MB-468 ₅₀)。

4. N of table, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine and its homologue inhibiting effect that human colon cancer cell MDA-MB-468 is increased

Embodiment	3	4	5	11	12	18
IC 50(nm)	1865	950.4	> 10 5	> 10 5	236.1	> 10 5
Embodiment	20	21	22	23	27	29
IC 50(nm)	122.2	372.1	422.4	54.12	452.1	860.2
Embodiment	30	31	37	44	45	46
IC 50(nm)	10 μM of >	334.8	4709	183.3	106.2	929.6
Embodiment	47	48	49	50	51	52
IC 50(nm)	145.2	160.8	1578	> 10 5	3679	523.0
Embodiment	53	54	57	58	59	64
IC 50(nm)	> 10 5	> 10 5	14.96	68.81	6.61	> 10 4
Embodiment	66	67	68	69	70	71
IC 50(nm)	429.9	> 10 5	> 10 5	> 10 4	> 10 5	> 10 5
Embodiment	72	73	74	75	76	77

IC 50(nm)	103.5	209.6	304.7	167.6	262.3	937.4
Embodiment	80	81	82	83	84	85
IC 50(nm)	270.6	201.4	200.5	73.36	245.8	22.16
Embodiment	90	AZD0156
IC 50(nm)	> 10 4	10.93

Therefore, it is measured through MTT detection method, N, N- dimethyl -3- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine (embodiment 23) and its homologue have inhibiting effect to the growth of MDA-MB-468 cell.Plurality of embodiment, such as embodiment 57, the inhibiting effect increased to MDA-MB-468 cell are suitable with AZD0156.

Although having adequately described the present invention, it should be appreciated to those skilled in the art that identical implementation can be carried out within the scope of extensive and equivalent condition, preparation and other parameters in the case where not influencing the scope of the invention or its any embodiment.All patents, patent application and publication cited herein is all incorporated herein by reference.

Claims (11)

1. The compound of Formulas I or its officinal salt or prodrug:

   Wherein, A ₁And A ₂It is respectively independently C or N；Preferably, A ₁For N；

   A ₃And A ₄It is respectively independently N, O, S or CR '；

   Including A ₁-A ₄A ring be containing 1-3 is heteroatomic can substituted 5 unit's heteroaryl；

   B ₁-B ₃Respectively stand alone as N or CR "；Preferably, B ₁For CH；

   D ₁-D ₄Respectively stand alone as N or CR " '；Preferably, D ₁-D ₄For CR " '；

   R ₁It is that can be substituted alkyl, alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl；

   R ₂It is hydrogen, it can substituted alkoxy, amino, carbocylic radical, heterocycle, aryl or heteroaryl；

   R ', R ", R " ' and R ₃Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl and carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group；Preferably, R ₃It is hydrogen.
2. The compound of claim 1, wherein for the compound of Formula II or its officinal salt or prodrug:

   Wherein, A ₂-A ₄, B ₂-B ₃, D ₁-D ₄And R ₁-R ₃As defined in claim 1；

   R ₄Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl and carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group；Preferably, R ₄For H.
3. The compound of claims 1 or 2, wherein for the compound of formula III a or formula III b or its officinal salt or prodrug:

   Wherein, A ₂-A ₄, B ₂-B ₃, D ₁, D ₃-D ₄And R ₁-R ₄As claims 1 or 2 defines；

   For formula III b, R ₅-R ₈Stand alone as hydrogen, halogen, can substituted amino, can substituted alkoxy, can substituted C _1-10Alkyl (such as alkylhalide group, hydroxy alkyl, aminoalkyl and carboxyalkyl), alkenyl, alkynyl, nitro, cyano, acylamino-, hydroxyl, sulfydryl, acyloxy, azido, carboxyl, ethylene oxygroup, alcohol amide base or can substituted alkylthio group；

   Preferably, R ₃And R ₄It is hydrogen, R ₅-R ₈It is hydrogen, halogen or alkylhalide group.
4. The compound of claims 1 or 2, wherein the compound of preferably formula III b or its officinal salt or prodrug, wherein A ₂For C；A ₃And A ₄For N；B ₂For CH；B ₃For N or CH；R ₆For alkylhalide group or halogen；R ₅、R ₇And R ₈For H or halogen；R ₁For can substituted heterocycle；R ₂For can substituted heterocycle, or by-NR ₉R ₁₀Substituted C _1-6Alkoxy；Wherein, R ₉And R ₁₀Stand alone as hydrogen or C _1-6Alkyl.Preferably, B ₃For N or CH；R ₆For CF ₃, F, Cl or Br, R ₅、R ₇And R ₈For H or halogen；R ₂For can substituted heterocycle, or by-NR ₉R ₁₀Substituted C _1-6Alkoxy.
5. The compound of claim 1, wherein the compound is selected from:

   N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [2,3-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- ((6- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridin-3-yl) oxygroup) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrimidine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- ((2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrimidine -5- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyrazine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -2- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) ethamine；

   N- (3- (dimethylamino) propyl) -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) aniline；

   N- (3- (dimethylamino) propyl)-N- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) aniline；

   N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   8- (4- (4- methylpiperazine-1-yl) phenyl) -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline；

   1- (tetrahydro -2H- pyrans -4- base) -8- (4- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) phenyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline；

   N, N- dimethyl -1- (5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) piperidines -4- amine；

   8- (6- (4- methylpiperazine-1-yl) pyridin-3-yl) -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline；

   1- (tetrahydro -2H- pyrans -4- base) -8- (6- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyridin-3-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline；

   N, N- dimethyl -4- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) cyclohexylamine；

   N, N- dimethyl -4- (5- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) cyclohexylamine；

   N, N- dimethyl -3- (4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- morpholinyl-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (4- methylpiperazine-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- morpholinyl-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- (4- methylpiperazine-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (1H- imidazoles -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (1H- imidazol-4 yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- ((5- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) pyridine -2- base) oxygroup) -1- propylamine；

   N, N- dimethyl -3- (4- (1- morpholinyl imidazo [1,5-c] quinazoline -9- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,5-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) imidazo [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) H- pyrrolo- [1,2-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   8- phenyl -1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline；

   N, N, N- trimethyl -3- ((4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) amino) -1- propylamine salt；

   1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N- methyl-1-(4- (1- (tetrahydro-2H- pyrans-4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- trifluoromethyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 3- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 3- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (3- methyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (3- trifluoromethyl -4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (6- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) pyridin-3-yl) piperidines -4- amine；

   N, N- dimethyl -1- (1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidin-4-yl) methylamine；

   N, N- dimethyl -2- (1- (4- (1- (tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidin-4-yl) -1- ethamine；

   N, N- dimethyl -3- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the chloro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- trifluoromethyl -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- trifluoromethyl -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 6- trifluoromethyl -4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 6- trifluoromethyl -4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (4- (1- (4- (dimethyl amido) piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N- methyl-1-(4- (1- (morpholinyl methyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine；

   8- phenyl -1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine；

   N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenyl) methylamine；

   N, N- dimethyl -3- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenoxy group) -1- propylamine；

   N- methyl-1-(4- (1- (tetrahydro-2H- pyrans-4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-8- base) phenyl) piperidines-4- amine；

   N, N- dimethyl -1- (4- (1- (tetrahydro -2H- pyrans -4- base) pyrido [3,4-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N- methyl-1-(4- (9- (tetrahydro-2H- pyrans-4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (5- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) pyridine -2- base) piperidines -4- amine；

   N- methyl-1-(4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) pyridine-2- base) piperidines-4- amine；

   N, N- dimethyl -1- (4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (4- (9- (morpholinyl methyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the chloro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- trifluoromethyl -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- trifluoromethyl -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 6- trifluoromethyl -4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 6- trifluoromethyl -4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine；

   N, N- dimethyl -1- (2- (the fluoro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine；

   N, N- dimethyl -1- (2- (the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine；

   N, N- dimethyl -1- (2- (3- trifluoromethyl -4- (4- (dimethylamino) piperidin-1-yl) phenyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -9- base) piperidines -4- amine；

   9- (6- (3- (dimethylamino) propoxyl group) pyridin-3-yl)-3- methyl-1-(tetrahydro-2H- pyrans-4- base) pyrazolo [1,5-c] quinazoline-2 (3H) -one；

   N- methyl-1-(the fluoro- 4- of 2- (1- ((3S, 5R)-3,4,5- tri methyl piperazine-1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine；

   N- methyl-1-(2- (trifluoromethyl)-4- (1- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (the fluoro- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N- ethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3S, 5R) -4- isopropyl -3,5- lupetazin -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (the fluoro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the chloro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N- methyl-1-(2- (trifluoromethyl)-4- (1- ((2S, 6R)-2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline-8- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (2- (trifluoromethyl) -4- (1- ((2S, 6R) -2,6- dimethylated morpholinyl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- (piperidin-1-yl)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (1- ((3R, 5S) -3,5- lupetidine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (1- ((3R, 5S) -3,5- lupetidine -1- base)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   N- methyl-1-(the fluoro- 4- of 2- (9- ((3S, 5R)-3,4,5- tri methyl piperazine-1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine；

   N- methyl-1-(2- (trifluoromethyl)-4- (9- ((3S, 5R)-3,4,5- tri methyl piperazine-1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (the fluoro- 4- of 2- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N- ethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -3,4,5- tri methyl piperazine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -4- ethyl -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3S, 5R) -4- isopropyl -3,5- lupetazin -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N- methyl-1-(2- (trifluoromethyl)-4- (9- ((2S, 6R)-2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine-2- base) phenyl) piperidines-4- amine；

   N- ethyl -1- (2- (trifluoromethyl) -4- (9- ((2S, 6R) -2,6- dimethylated morpholinyl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((2R, 6S) -2,6- dimethyl tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- (piperidin-1-yl) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (2- (trifluoromethyl) -4- (9- ((3R, 5S) -3,5- lupetidine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- ((3R, 5S) -3,5- lupetidine -1- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (the fluoro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the chloro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- trifluoromethyl -4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (the fluoro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the chloro- 4- of 2- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (2- (trifluoromethyl) -4- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -1- (the fluoro- 4- of 3- (9- (tetrahydro -2H- pyrans -4- base) pyrido [3,2-e] [1,2,4] triazole simultaneously [4,3-a] pyrazine -2- base) phenyl) piperidines -4- amine；

   N, N- dimethyl -3- (the bromo- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the fluoro- 4- of 3- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- fluoro- 6- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (2- chloro- 6- (trifluoromethyl) -4- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -3- (the fluoro- 4- of the chloro- 3- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenoxy group) -1- propylamine；

   N, N- dimethyl -1- (the bromo- 4- of 2- (1- ((3S, 5R) -3,4,5- tri methyl piperazine -1- bases)-[1,2,4] triazole simultaneously [4,3-a] quinoxaline -8- base) phenyl) piperidines -4- amine；

   Or its officinal salt or prodrug.
6. Compound according to any one of claims 1 to 5 treats or prevents the disease due to caused by DDR functional defect in preparation or benefits from the purposes in the repressed drug of kinase activity；Preferably, the disease is cancer.
7. The purposes of claim 6, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin lymphoma, acute lymphatic leukaemia, chronic lymphocytic leukemia, Huppert's disease, neuroblastoma, breast cancer, oophoroma, lung cancer, wilms' tumor, cervix cancer, carcinoma of testis, soft tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinaemia, bladder cancer, chronic myelocytic leukemia, primary brain cancer, chromoma, Small Cell Lung Cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid carcinomas, chromoma, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, cancer of pancreas, acute myeloblastic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi sarcoma, urogenital neoplasm, thyroid cancer, the cancer of the esophagus, malignant hypercalcemia , hyperplasia of cervix uteri disease, clear-cell carcinoma, carcinoma of endometrium, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, cutaneum carcinoma or prostate cancer.
8. The purposes of claim 7, wherein further include anticancer drug known at least one or the anticancer drug to drug officinal salt；Preferably, institute includes at least one anticancer drug selected from the group below: busulfan to drug, melphalan, Chlorambucil, cyclophosphamide, ifosfamide, Temozolomide, bendamustine, cis-platinum, mitomycin C, bleomycin, carboplatin, camptothecine, Irinotecan, Hycamtin, adriamycin, Epi-ADM, aclacinomycin, mitoxantrone, methyl hydroxy ellipticine, etoposide, 5-azacitidine, gemcitabine, 5 FU 5 fluorouracil, methotrexate (MTX), the fluoro- 2 '-uracil deoxyriboside of 5-, fludarabine, nelarabine, cytarabine, Alanosine, Pralatrexate, pemetrexed, hydroxycarbamide, thioguanine, colchicin, vincaleukoblastinum, vincristine, vinorelbine, taxol, Ipsapirone, Cabazitaxel, docetaxel, monoclonal antibody, Victibix, Ofatumumab , Avastin, Trastuzumab, Mabthera, Imatinib, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sutent, nilotinib, Dasatinib, pazopanib, special cancer is suitable, everolimus, Vorinostat, sieve miaow ester peptide, tamoxifen, Letrozole, fulvestrant, mitoguazone, Octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, Sa Li polyamines, lenalidomide, Venetoclax, Aldesleukin (RhIL-2), Sipueucel-T (prostate cancer therapy vaccine), Pa Boxini, olaparib, Niraparib, Rucaparib or Talazoparib.
9. The purposes of claim 7, wherein the drug and radiotherapy are combined.
10. A kind of Pharmaceutical composition, including compound according to any one of claims 1 to 5 and pharmaceutical acceptable carrier.
11. The Pharmaceutical composition of claim 10, wherein the composition also contains the officinal salt of anticancer drug known at least one or the anticancer drug；Preferably, the composition also contains at least one anticancer drug selected from the group below: busulfan, melphalan, Chlorambucil, cyclophosphamide, ifosfamide, Temozolomide, bendamustine, cis-platinum, mitomycin C, bleomycin, carboplatin, camptothecine, Irinotecan, Hycamtin, adriamycin, Epi-ADM, aclacinomycin, mitoxantrone, methyl hydroxy ellipticine, etoposide, 5-azacitidine, gemcitabine, 5 FU 5 fluorouracil, methotrexate (MTX), the fluoro- 2 '-uracil deoxyriboside of 5-, fludarabine, nelarabine, cytarabine, Alanosine, Pralatrexate, pemetrexed, hydroxycarbamide, thioguanine, colchicin, vincaleukoblastinum, vincristine, vinorelbine, taxol, Ipsapirone, Cabazitaxel, docetaxel, monoclonal antibody, Victibix, Ofatumum Ab, Avastin, Trastuzumab, Mabthera, Imatinib, Gefitinib, Erlotinib, Lapatinib, Sorafenib, Sutent, nilotinib, Dasatinib, pazopanib, special cancer is suitable, everolimus, Vorinostat, sieve miaow ester peptide, tamoxifen, Letrozole, fulvestrant, mitoguazone, Octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, Sa Li polyamines, lenalidomide, Venetoclax, Aldesleukin (RhIL-2), Sipueucel-T (prostate cancer therapy vaccine), Pa Boxini, olaparib, Niraparib, Rucaparib or Talazoparib.